Compositions and methods for treating pelvic pain and other conditions

ABSTRACT

Methods are provided for treating conditions including chronic pelvic pain, in which there are palpable trigger points of local areas of muscle restriction and spasticity that recreate or refer pain of patients complaints upon palpation, chronic pelvic pain syndrome, pelvic floor myalgia, pelvic floor dysfunction, interstitial cystitis, levator ani syndrome, coccygodynia, prostatodynia, piriformis syndrome, anal sphincter pain, bowel movement pain, post bowel movement pain, ejaculatory pain, post ejaculatory pain, sitting pain, post bowel movement pain, rectal pain, tailbone pain, urinary frequency, urinary urgency, urinary hesitancy, post urinary pain, overactive bladder, perineal pain, penile pain, vaginismus, anismus, sexual dysfunction, reduced level of ejaculate or reduced penile erection, myofascial pain in muscle tissue of a patient who has one or more trigger points in the muscle tissue, or the pain/sensitivity of pelvic floor muscle trigger points and specific areas of myofascial restriction detected upon palpation in a patient comprising administering to the one or more trigger points of the patient in need thereof a therapeutically effective amount of a calcium channel blocker, or L-arginine, or a combination of a calcium channel blocker and L-arginine, or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof; the application of the topical form of the drug can be applied by the patient regularly as part of a self treatment program to heal muscle related pain and muscle related pelvic pain and each optionally together with a corticosteroid such as cortisone of hydrocortisone. The invention further provides methods for myofascial release, trigger point release, and the use of dilators with and without calcium channel blockers for pain conditions. The invention further provides pharmaceutical compositions, kits and applicator devices useful in the methods of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. ProvisionalApplications Ser. No. 61/886,244 filed Oct. 3, 2013; 61/898,095 filedOct. 31, 2013; 61/924,635 filed Jan. 7, 2014; 61/936,031 filed Feb. 5,2014; 61/982,614 filed Apr. 22, 2014; 62/014,945 filed Jun. 20, 2014 and62/051,249, filed Sep. 16, 2014. The entire disclosures of each of theforegoing applications is incorporated herein by reference in theirentireties.

BACKGROUND

The disclosure herein relates to drugs, drug delivery devices, andmethods for treating pain conditions, and in particular pelvic pain, inwomen and men

Pelvic pain has long been a problem among women and men. Conventionalmedicine has treated pelvic pain in various ways including, 1) anorgan-specific focus in which pelvic pain is believed to be a symptom ofinflammation in the bladder, inflammation or infection in the prostategland, or pathology of the uterus; 2) focus on the idea of the pudendalnerve being entrapped and needing release; 3) focus on an autoimmuneprocess; or 4) focus supposed on psychiatric problems, a propensitytoward malingering, or neurotic somatization.

The approaches described above are based on a misunderstanding of thenature of most cases of pelvic pain. In recent years, evidence hasemerged that a large majority of pelvic pain in men and women is relatedto the presence of trigger points and myofascial dysfunction and triggerpoint related myofascial pain. Understanding cases of pelvic pain asmuscle related pain is an entirely new paradigm in urology. This newunderstanding sees anxiety and sometimes injury producing trigger pointswithin muscles either at the surface of the muscle, inside the muscle,in the belly or the attachment of the muscle of the pelvic floor. Thesetrigger points are painful bands in muscle that can refer pain to remotesites, and when pressed skillfully recreate a patient's symptoms. Whenpressed in a specific way these trigger points can release, oftenattended by a significant reduction or abatement in pain anddysfunction. Pelvic floor trigger points and related myofascialrestriction have typically been found to be strongly exacerbated bymuscle overuse, local ischemia, psychological anxiety and otherperpetuating factors. Trigger point release, particularly for triggerpoints located on the outside of the body has become a subspecialtywithin medicine. The inventor of the present invention, David Wise,Ph.D., along with his colleague and co-author Rodney Anderson, M.D.,professor of urology at Stanford University, previously describedtechniques for identifying and releasing trigger points in their book AHeadache in the Pelvis: A New Understanding and Treatment forProstatitis and Chronic Pelvic Pain Syndromes, which was originallypublished by the National Center for Pelvic Pain Research in 2003, andis incorporated herein by reference in its entirety. He is an author offour other peer-reviewed articles on this subject.

Topical nifedipine has been reported for use in anal fissure andvulvodynia. See e.g., Bornstein, J. et al., J. Pain 2010 11(12):1403-1409. A clinical trial also is ongoing for the use of vaginalnifedipine as an adjunct to conventionally delivered pelvic floorphysical therapy for levator myalgia and pelvic pain. See Clinical TrialNo. NCT01586286 (Vanderbilt Univ.) at clinicaltrials.gov. However, thesestudies neither describe nor suggest the specific application of calciumchannel blockers or L-arginine to specific muscle trigger points; or theuse of the compounds as disclosed herein.

In an age where there is an epidemic of the use of narcotic medicationto treat pelvic pain, there exists an ongoing need for more efficacioustreatments for the pain conditions described above. This invention isdirected to these, as well as other, important ends.

SUMMARY

Drugs, drug delivery devices, and methods for treating pelvic pain aretaught herein.

In one aspect, methods are provided for treating, reducing, resolving,eliminating, and/or preventing prostatitis category IIIA and/or IIIB ina male patient. In some embodiments, the method comprises administeringto the male patient in need thereof a therapeutically effective amountof a calcium channel blocker (also known as a calcium channelantagonist), or L-arginine, or a combination of a calcium channelblocker and L-arginine, or pharmaceutically acceptable salts, hydrates,solvates and prodrugs thereof.

In a further aspect, methods are provided for treating, reducing,resolving, eliminating, and/or preventing chronic pelvic pain, chronicpelvic pain syndrome, pelvic floor myalgia, pelvic floor dysfunction,interstitial cystitis, levator ani syndrome, coccygodynia,prostatodynia, prostadynia, piriformis syndrome, anal sphincter pain,bowel movement pain, post bowel movement pain, overactive bladder,ejaculatory pain, ejaculatory discomfort, post ejaculatory pain, sittingpain, rectal pain, tailbone pain, urinary frequency, urinary urgency,urinary hesitancy, perineal pain, penile pain, vaginismus, anismus,sexual dysfunction, anal fissures, reduced level of ejaculate or reducedpenile erection, nonbacterial prostatitis, slow urinary flow, reducedurinary flow, post ejaculatory discomfort, myofascial pain in muscletissue of a patient who has one or more trigger points in the muscletissue, or the pain/sensitivity of pelvic floor muscle trigger pointsand specific areas of myofascial restriction detected upon palpation ina patient.

In a further aspect, methods are provided for reducing or resolvingtrigger point activity in a muscle of a patient comprising contactingthe muscle with a therapeutically effective amount of a calcium channelblocker, or L-arginine, or a combination of a calcium channel blockerand L-arginine, or pharmaceutically acceptable salts, hydrates, solvatesand prodrugs thereof.

In a further aspect, the methods of the invention as described hereininclude administering to the patient in need thereof a therapeuticallyeffective amount of a calcium channel blocker, or L-arginine, or acombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof, optionally together with a corticosteroid, for examplecortisone or cortisol.

In a further aspect, the methods of the invention described hereininclude treating a patient in need thereof with a dilator, such as ananal, vaginal or urethral dilator (including pediatric dilatorsthereof). In a further embodiment, treatment with such dilators mayfurther comprise the oral or topical administration of one or morecalcium channel blockers, or pharmaceutically acceptable salts,hydrates, solvates or prodrugs thereof.

In some further embodiments, methods are provided for treating urinarysphincter spasm and post urinary pain; and for treating proctalgiafugax, comprising administering to a patient in need thereof atherapeutically effective amount of a calcium channel blocker, forexample nifedipine or diltiazem, or pharmaceutically acceptable salts,hydrates, solvates and prodrugs thereof. In some embodiments, thecalcium channel blocker or pharmaceutically acceptable salts, hydrates,solvates and prodrugs thereof is administered orally, and in someembodiments, the calcium channel blocker or pharmaceutically acceptablesalts, hydrates, solvates and prodrugs thereof is administeredtopically.

In some embodiments, a topical pharmaceutical composition is applied tospecific areas of the anal sphincter, vaginal opening, and/or specificareas of trigger pointed tissue in the pelvic floor muscles of thepatient. In some embodiments, the topical pharmaceutical composition isapplied using a pressure applicator device, which is inserted into therectal cavity or vaginal cavity of a human patient through the analsphincter or vaginal opening and is used to apply a topicalpharmaceutical composition. The pressure applicator device is insertedbeyond the internal anal sphincter or inside the vagina to a distancewhere a finger cannot typically reach and pressure is applied at aninternal trigger point within the rectal cavity or the vaginal cavitywith the pressure applicator device to apply the topical pharmaceuticalcomposition. In addition to treatment by a professional therapist, thisalso allows for patient self-treatment, enabling a patient with noaccess to a pelvic floor specialist to self-administer treatment.

In some embodiments, the application of topical pharmaceuticalcompositions is assisted by the use of a drug applicator sleeve. Thissleeve fits around the pressure applicator and allows the patient ortherapist to apply compositions directly to the point of pressureapplication within the vaginal or rectal cavity.

In some embodiments, the methods of the invention involve oral, topicalor injectable administration of the calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof, optionally together with a corticosteroid and/or ananesthetic.

In a further aspect, the invention provides methods for relieving musclesoreness or pain comprising applying to the muscle a topical compositioncomprising a calcium channel blocker, or a pharmaceutically acceptablesalt, hydrate, solvate or prodrug thereof.

In a further aspect, the invention provides methods for relieving one ormore symptoms of carpal tunnel syndrome, comprising administering apharmaceutical composition comprising a calcium channel blocker, or apharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The description herein makes reference to the accompanying drawings,wherein like reference numerals refer to like parts throughout theseveral views, and wherein:

FIG. 1A is an illustration showing a first example drug delivery deviceand a pressure applicator in a first position;

FIG. 1B is an illustration showing the first example drug deliverydevice and the pressure applicator in a second position;

FIG. 2 is an illustration showing a second example drug delivery device;

FIG. 3 is an illustration showing a third example drug delivery device;

FIG. 4 is an illustration showing a fourth example drug delivery device;

FIG. 5A is an illustration showing a fifth example drug delivery deviceand the pressure applicator in a first position;

FIG. 5B is an illustration showing the fifth example drug deliverydevice and the pressure applicator in a second position;

FIG. 6A is an illustration showing a sixth example drug delivery deviceand the pressure applicator in a first position;

FIG. 6B is an illustration showing the sixth example drug deliverydevice and the pressure applicator in a second position;

FIG. 7A is an illustration showing a seventh example drug deliverydevice and the pressure applicator in a first position; and

FIG. 7B is an illustration showing the seventh example drug deliverydevice and the pressure applicator in a second position.

FIG. 8A is an illustration showing an embodiment of the drug applicatorsleeve of the invention; and

FIGS. 8B, 8C and 8D are illustrations showing further embodiments of thedrug applicator sleeve of the invention.

FIG. 9 shows an internal trigger point wand 400 inserted into a drugapplicator sleeve of the invention.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there is aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, the term “active agent” or “active ingredient” isintended to mean a calcium channel blocker as described herein, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof. In some embodiments, the active agent or activeingredient optionally also can include a corticosteroid, for examplecortisone or hydrocortisone (cortisol), for management of inflammation.The active agent can be administered to a patient in anypharmaceutically acceptable and effective form, for example by injectionor topically via creams, gels, ointments, emulsions, solutions, lotions,suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays,suppositories, or any other formulations or pharmaceutical compositionssuitable for topical administration; or orally via any formulation orpharmaceutical composition suitable for oral administration, such astablets, pills, capsules, and the like.

As used herein, reference to specific types of compounds, for examplecalcium channel blockers, and specific compounds, for examplenifedipine, diltiazem and L-arginine, are intended to includepharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism. Seee.g., (Guillory, K., Chapter 5, pp. 183-226; specifically 202-205 inPolymorphism in Pharmaceutical Solids, (Brittain, H. ed.), MarcelDekker, Inc., New York, N.Y., 1999). The above methods for preparinghydrates are well within the ambit of those of skill in the art, arecompletely conventional and do not require any experimentation beyondwhat is typical in the art. Hydrates may be characterized and/oranalyzed by methods well known to those of skill in the art such as, forexample, single crystal X-Ray diffraction, X-Ray powder diffraction,Polarizing optical microscopy, thermal microscopy, thermogravimetry,differential thermal analysis, differential scanning calorimetry, IRspectroscopy, Raman spectroscopy and NMR spectroscopy. (Brittain, H.,Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids,(Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition,many commercial companies routine offer services that includepreparation and/or characterization of hydrates such as, for example,HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil,France (http://www.holodiag.com).

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecalcium channel blocker or L-arginine in a preventative fashion. Theapplication of a therapeutic for preventing or prevention of a diseaseof disorder is known as ‘prophylaxis.’ In some embodiments, the calciumchannel blocker or L-arginine provided herein provide superiorprophylaxis because of lower long term side effects over long timeperiods.

“Prodrug” refers to a derivative of a calcium channel blocker orL-arginine precursor that requires a transformation within the body torelease the active drug. Prodrugs are frequently (though notnecessarily) pharmacologically inactive until converted to the parentdrug.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. In some embodiments, the salts are pharmaceutically acceptable.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, but are not limited to, storage in an atmosphere containing asolvent, dosage forms that include the solvent, or routinepharmaceutical processing steps such as, for example, crystallization(i.e., from solvent or mixed solvents) vapor diffusion, etc. Solvatesmay also be formed, under certain circumstances, from other crystallinesolvates or hydrates upon exposure to the solvent or upon suspensionmaterial in solvent. Solvates may crystallize in more than one formresulting in solvate polymorphism. See e.g., (Guillory, K., Chapter 5,pp. 183-226; specifically 205-208 in Polymorphism in PharmaceuticalSolids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, N.Y., 1999)).The above methods for preparing solvates are well within the ambit ofthose of skill in the art, are completely conventional do not requireany experimentation beyond what is typical in the art. Solvates may becharacterized and/or analyzed by methods well known to those of skill inthe art such as, for example, single crystal X-Ray diffraction, X-Raypowder diffraction, Polarizing optical microscopy, thermal microscopy,thermogravimetry, differential thermal analysis, differential scanningcalorimetry, IR spectroscopy, Raman spectroscopy and NMR spectroscopy.(Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in PharmaceuticalSolids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). Inaddition, many commercial companies routine offer services that includepreparation and/or characterization of solvates such as, for example,HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil,France (http://www.holodiag.com).

“Patient” refers to a vertebrate, preferably a mammal. Mammals include,but are not limited to, murines, rodents, simians, humans, farm animals,sport animals and pets.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). Treatment may also be considered to includepreemptive or prophylactic administration to ameliorate, arrest orprevent the development of the disease or at least one of the clinicalsymptoms. In a further feature the treatment rendered has lowerpotential for long-term side effects over multiple years. In otherembodiments “treating” or “treatment” refers to ameliorating at leastone physical parameter, which may not be discernible by the patient. Inyet other embodiments, “treating” or “treatment” refers to inhibitingthe disease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In yet other embodiments, “treating” or“treatment” refers to delaying the onset of the disease or disorder.

The term “contacting” is intended to mean causing the coming together ofthe items to be contacted. For example, “contacting” a muscle with acalcium channel blocker in accordance with the methods of the inventionwould include any action resulting in the physical contact of thecalcium channel blocker with the muscle, for example, local (e.g., byinjection) topical, or oral administration of the calcium channelblocker to a patient.

The term “administering” and “applying to the patient” as used inconnection with the methods of the invention is intended to includeoral, injection, and topical modes of introducing the active ingredientsof the invention to the body of a patient by, for example, the selftreating patient, physician, physical therapist or other appropriatehealth care provider.

“Therapeutically effective amount” means the amount of a calcium channelblocker or L-arginine or combination thereof that, when administered toor administered by a patient for treating a disease or condition asdescribed herein, is sufficient to effect such treatment for thedisease. The “therapeutically effective amount” will vary depending onthe calcium channel blocker or L-arginine, the disease and its severityand the age, weight, adsorption, distribution, metabolism and excretionetc., of the patient to be treated.

It has been discovered in accordance with the present invention that theadministration of calcium channel blockers, for example diltiazem andnifedepine, or the administration of L-arginine, either alone or incombination with a calcium channel blocker, can treat pain in a varietyof diseases, disorders or conditions. While not wishing to be bound byany particular theory, it is believed that such pain, for example pelvicpain, is caused in many instances by chronically trigger pointed orchronically myofascially restricted muscle. Treatment of the affectedmuscle, and especially the specific trigger points or myofasciallyrestricted areas thereof, with a calcium channel blocker such asnifedipine or diltiazem in accordance with the present invention, canameliorate the pain condition.

Thus, in one embodiment, the present invention provides methods forreducing or resolving trigger point activity in muscle of a patient inneed thereof comprising contacting the muscle with a therapeuticallyeffective amount of a calcium channel blocker, or L-arginine, or acombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof. The calcium channel blocker, L-arginine, or combination thereofadministered can be administered to one or more external or internaltrigger points of the muscle manually, or using an applicator such as asyringe or an internal trigger point wand as described below, or viaoral administration, or via injection.

In some embodiments, the calcium channel blocker, or L-arginine, or acombination of calcium channel blocker and L-arginine, is administeredin a topical formulation intrarectally. As discussed below, suchintrarectal administration involves placement of the topical formulationeither with an anal syringe, suppository or with a finger up to andslightly past the internal anal sphincter, and also includes theplacement and application with an internal trigger point wand andoptionally a covering that allows for administration of the medicationbeyond the internal sphincter into the pelvic floor to reach the levatorani, coccygeus, obturator internus, piriformis, and other pelvic floormuscles in pain with chronic pelvic pain related syndromes, as opposedto perirectal administration, which has been used for example forapplication of topical formulations to anal fissures, and involvesplacement of a topical formulation within the first 1 cm of the analcanal. See Golfam, F., et al., The Effect of Topical Nifedipine inTreatment of Chronic Anal Fissure, Acta Medica Iranica, Vol. 48, No. 5(2010), p. 295-299.

As described above, the calcium channel blocker, or L-arginine, or acombination of calcium channel blocker and L-arginine, can administeredvia injection, which is preferably, but not necessarily, an injectiondirectly into, near to or adjacent to one or more specific triggerpoints in the muscle; for example the pelvic floor muscles, or externalmuscles such as, for example, the rectus abdominus, gluteal and adductormuscles or quadratus lumborum of the patient. At the present time, drugssuch as bupivacaine (markaine), cortisone and botox have been injectedinto trigger points with little utility. While not wishing to be boundby any particular theory, it is believed that the vasodilative action ofthe calcium channel blockers, or the action of L-arginine, as describedherein, may reduce the pain or deactivate the trigger point.Significantly, the use of calcium channel blockers as described hereinmay possess the advantage of not having to be injected directly into atrigger point, but rather injected in the area adjacent to the triggerpoint, with the result that the vasodilation and relaxation of thespecific area may deactivate the trigger points.

Thus, the methods of the invention find use in treating a variety ofdiseases, disorders and pain conditions including pelvic pain disorders,such as prostatitis category IIIA and/or IIIB in a male patient, chronicpelvic pain, pelvic floor muscles with trigger points or areas ofmyofascial restriction, chronic pelvic pain syndrome, pelvic floormyalgia, pelvic floor dysfunction, interstitial cystitis, levator anisyndrome, coccygodynia, prostatodynia, prostadynia, piriformis syndrome,anal sphincter pain, bowel movement pain, post bowel movement pain,ejaculatory pain, ejaculatory discomfort, post ejaculatory pain, sittingpain, rectal pain, tailbone pain, urinary frequency, urinary urgency,urinary hesitancy, perineal pain, penile pain, vaginismus, anismus,sexual dysfunction, reduced level of ejaculate or reduced penileerection, nonbacterial prostatitis, slow urinary flow, reduced urinaryflow, post ejaculatory discomfort, urinary or urethral sphincter spasmsand post urinary pain, rectal sphincter spasms, proctalgia fugax,myofascial pain in muscle tissue of a patient who has one or moretrigger points in the muscle tissue, and the pain/sensitivity of pelvicfloor muscle trigger points and specific areas of myofascial restrictiondetected upon palpation in a patient.

In some embodiments, the methods comprise orally or topicallyadministering to a patient in need thereof a therapeutically effectiveamount of a calcium channel blocker, for example nifedipine ordiltiazem, or L-arginine, or a combination of a calcium channel blockerand L-arginine, or pharmaceutically acceptable salts, hydrates, solvatesand prodrugs thereof.

In some preferred embodiments, the calcium channel blocker, L-arginineor combination of calcium channel blocker, and L-arginine is appliedlocally in a topical formulation, preferably in an ointment that willminimize systemic spread of the active ingredient(s), and at aconcentration that is uniquely effective for treating the pain conditionand reducing the likelihood of the calcium channel blocker becomingsignificantly systemically absorbed. In some embodiments, the calciumchannel blocker, L-arginine or combination thereof is applied by usingan applicator, for example a syringe, probe or pressure applicator suchas an internal trigger point wand, as described below. In some suchembodiments, the calcium channel blocker, L-arginine or combinationthereof is administered through the use of a drug applicator sleeve thatsurrounds the syringe, probe or pressure applicator. In some furtherpreferred embodiments, the calcium channel blocker, L-arginine orcombination of calcium channel blocker, and L-arginine is administeredorally as described below. In still further embodiments, the calciumchannel blocker, L-arginine or combination of calcium channel blocker,and L-arginine is administered via injection, preferably at or near thepelvic floor muscle trigger points and/or specific areas of myofascialrestriction.

Accordingly, in one aspect, the present application describes methods(Method 1) for treating, reducing, resolving, eliminating, and/orpreventing prostatitis category IIIA and/or IIIB in a male patient. Insome embodiments, the methods comprise administering to the male patientin need thereof a therapeutically effective amount of a calcium channelblocker, or L-arginine, or a combination of a calcium channel blockerand L-arginine, or pharmaceutically acceptable salts, hydrates, solvatesand prodrugs thereof.

In a further aspect, methods are provided for treating, reducing,resolving, eliminating, and/or preventing chronic pelvic pain, pelvicfloor muscles containing trigger points and areas of myofascialrestriction, chronic pelvic pain syndrome, pelvic floor myalgia, pelvicfloor dysfunction, interstitial cystitis, levator ani syndrome,coccygodynia, prostatodynia, prostadynia, piriformis syndrome, analsphincter pain, bowel movement pain, ejaculatory pain, ejaculatorydiscomfort, post ejaculatory pain, sitting pain, post bowel movementpain, rectal pain, tailbone pain, urinary frequency, urinary urgency,urinary hesitancy, perineal pain, penile pain, sexual dysfunction,reduced level of ejaculate or reduced penile erection, nonbacterialprostatitis, slow urinary flow, reduced urinary flow, post ejaculatorydiscomfort, vaginismus, anismus, anal fissures or tear in theanorectal/anal sphincter area, myofascial pain in muscle tissue of apatient who has one or more trigger points in the muscle tissue, or thepain/sensitivity of pelvic floor muscle trigger points and specificareas of myofascial restriction detected upon palpation in a patient. Insome embodiments, the methods comprise administering to the patient inneed thereof a therapeutically effective amount of a calcium channelblocker, or L-arginine, or a combination of a calcium channel blockerand L-arginine, or pharmaceutically acceptable salts, hydrates, solvatesand prodrugs thereof.

Post urinary pain is pain that occurs after urination. While not wishingto be bound by any particular theory, it is believed that the pain canresult from spasm in the urinary sphincter, and that administration,preferably oral administration, and even more preferably extendedrelease oral administration, of a calcium channel blocker, for examplenifedipine or diltiazem, or a pharmaceutically acceptable salt, hydrate,solvate or prodrug thereof in accordance with the methods of theinvention, will treat the condition—i.e., will prevent or reduce thepost urinary pain—by reducing the occurrence and/or intensity of spasmin the urinary sphincter.

Proctalgia fugax is a severe, episodic rectal spasm, which can occur atany time, but frequently occurs at night, and sometimes is verydistressing and frightening. While not wishing to be bound by anyparticular theory, it is believed that proctalgia fugax results fromspasm in the anal sphincter, rectum, or in the pubococcygeus or levatorani muscles. Thus, it is believed that administration, either oral ortopical, preferably oral administration, and even more preferablyextended release oral administration, of a calcium channel blocker, forexample nifedipine or diltiazem, or a pharmaceutically acceptable salt,hydrate, solvate or prodrug thereof in accordance with the methods ofthe invention, will treat the condition—i.e., will prevent or reduce thepain—by reducing the occurrence and/or intensity of spasm in the analsphincter, rectum, or in the pubococcygeus, levator ani muscles, orother pelvic floor muscles through reducing calcium in the calciumchannels of the muscles, especially in smooth muscle.

Thus, in some embodiments, the invention provides methods for treatingurinary sphincter spasms, urethral sphincter spasms, post urinary pain,rectal sphincter spasms, and proctalgia fugax; which methods preferablycomprise topical or oral administration, and preferably extended releaseoral administration, of a calcium channel blocker, for examplenifedipine or diltiazem, or a pharmaceutically acceptable salt, hydrate,solvate or prodrug thereof, to a patient in need of treatment.

In some embodiments, the invention provides methods for treating painconditions, for example chronic pelvic pain, chronic pelvic pain withoutfissures or fistulas, chronically trigger pointed pelvic floor muscles,chronic pelvic pain syndrome, pelvic floor myalgia, pelvic floordysfunction, interstitial cystitis, overactive bladder, levator anisyndrome, coccygodynia, prostatodynia, piriformis syndrome, analsphincter pain, bowel movement pain, post bowel movement pain,ejaculatory pain, post ejaculatory pain, sitting pain, rectal pain,tailbone pain, urinary frequency, urinary urgency, urinary hesitancy,perineal pain, penile pain, vaginismus, anismus, sexual dysfunction,reduced level of ejaculate or reduced penile erection, myofascial painin muscle tissue of a patient who has one or more trigger points in themuscle tissue, conditions characterized by muscle spasm or soreness,urinary sphincter spasms, urethral sphincter spasms, post urinary pain,rectal sphincter spasms and proctalgia fugax, or the pain/sensitivity ofpelvic floor muscle trigger points and specific areas of myofascialrestriction detected upon palpation in a patient, said method comprisinguse of one or more dilators. The dilator or dilators may include anal,vaginal or urethral dilators, and pediatric dilators. In someembodiments, the aforementioned chronic pelvic pain exists with orwithout fissures or fistulas or evidence of hypertonus or otherpathology in external or internal anal sphincters. In another particularembodiment, the chronic pelvic pain syndrome exists with pain containingor referring to trigger points.

Dilators for use in accordance with the methods of the invention arepreferably are preferably sized from ¼ inch in diameter to 1½″ inches indiameter, for example in size increments of 1/16 or ⅛ of an inch. Insome embodiments, treatment further comprises the progressivetransitioning from smaller sized dilators to larger sized dilators. Insome preferred embodiments, the methods of the invention comprise theuse of the dilators daily, or more than once daily, for example twicedaily, three times daily, or more, for a period of time at eachinstance, for example of from about 10 minute to about 40 minutes, orabout 20 minutes to about 30 minutes. The methods of the invention canbe employed for a fixed period of time, for example on a single day, forseveral days, a week, 1 month, or longer. In some embodiments, treatmentwith the methods of the invention is continued until symptoms areresolved.

The dilators for use in the methods of the invention may be of anysuitable shape or design, including any currently available to patientsand medical practitioners. The dilators may be made of any suitablematerial, including but not limited to, synthetic plastics and polymers,such as silicone, and metals. Use of the dilators in accordance with theinvention may optionally involve the use of lubricants. The use ofdilators in accordance with the methods of the invention can be by thepatient, or another, for example and a doctor, physical therapist orother health care professional.

In some embodiments, the methods of the invention comprise the use ofdilators as described above, and also include the administration of acalcium channel blocker, or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof, as described herein. Thecalcium channel blocker may be administered orally (e.g., as an oralcomposition), for example, in the form of a pill, tablet or capsule.Alternatively, the calcium channel blocker may be administered topically(e.g., as a topical composition), such as an ointment, gel or paste. Insome embodiments, the calcium channel blocker, or pharmaceuticalcomposition thereof, may be administered prior to use of the dilator,for example from 5 minutes to 60 minutes prior to dilator use, from 10minutes to 60 minutes prior to dilator use; from 20 minutes to 60minutes prior to dilator use; or from 30 to 60 minutes prior to dilatoruse. In some embodiments, a local anesthetic agent may also beadministered concomitantly or sequentially dilator use. Such localanesthetic may also be a component of the pharmaceutical compositioncontaining the calcium channel blocker, for example as in topicalcompositions as described herein. In some preferred embodiments, thecalcium channel blocker used with the dilator is nifedipine.

The use of both the calcium channel blocker, e.g. nifedipine, and thedilator uniquely addresses the problem of pain conditions bothmechanically and pharmacologically.

In some embodiments, the invention provides methods for relieving musclesoreness or pain in a patient in need thereof, comprising applying tothe muscle a topical composition comprising a calcium channel blocker ora pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.In some such embodiments, the topical composition is a balm, which cancomprise one or more analgesics, fragrances and excipients, for exampleand not limitation menthol, menthone, camphor, pulegol, isopulegol,cineole, mint oil, peppermint oil, spearmint oil, eucalyptus oil,3-(1-menthoxy)propane-1,2-diol, N-alkyl-p-menthane-3-carboxamide,2-methyl-3-(1-menthoxy)propane-1,2-diol, p-menthane-3,8-diol,2-(1-menthoxy)ethan-1-ol, 3-(1-menthoxy)propan-1-ol,4-(1-menthoxy)butan-1-ol, menthyl 3-hydroxybutanoate, menthyl lactate,menthone glycerin ketal, N-methyl-2,2-isopropylmethyl-3-methylbutaneamide, menthyl glyoxylate cajuput oil, clove oil, dementholized mint oiland paraffin petrolatum. Typically, balms are applied and massaged intothe intended muscle.

Carpal Tunnel Syndrome (CTS) is a median entrapment neuropathy thatcauses paresthesia, pain, numbness, and other symptoms in thedistribution of the median nerve due to its compression at the wrist inthe carpal tunnel. The main symptom of CTS is intermittent numbness ofthe thumb, index, long and radial half of the ring finger. Long-standingCTS leads to permanent nerve damage with constant numbness, atrophy ofsome of the muscles of the thenar eminence, and weakness of palmarabduction.

In some embodiments, the present invention provides methods forrelieving one or more symptoms of carpal tunnel syndrome in a patient inneed thereof, comprising administering to a patient in need thereof apharmaceutical composition comprising a calcium channel blocker, or apharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.In some such embodiments, a topical composition as described herein isapplied to the muscle. In other such embodiments, an oral pharmaceuticalcomposition as described herein is administered. While not wishing to bebound by any particular theory, it is believed that vasodilative actionof the calcium channel blockers may reduce the pain and soreness inmuscle, and also reduce, for example, numbness and pain in patientssuffering from carpal tunnel syndrome.

Overactive bladder is a urinary storage dysfunction that causes a suddenurge to urinate. Symptoms can include frequent urination, frequentinterruptions of sleep due to the need to urinate (nocturia), andurinating unintentionally followed by an urge to continue (urgeincontinence). In some embodiments, the present invention providesmethods for relieving one or more symptoms of overactive bladder,comprising administering to a patient in need thereof a pharmaceuticalcomposition comprising a calcium channel blocker, or a pharmaceuticallyacceptable salt, hydrate, solvate or prodrug thereof. While not wishingto be bound by any particular theory, it is believed that overactivebladder in many cases is in fact a symptom of pelvic floor dysfunction,and that the present methods described herein will find use ineffectively ameliorating the symptoms of overactive bladder.

Vaginismus is a condition in which an involuntary vaginal muscle spasmmakes any kind of vaginal penetration painful or impossible. Anismusrefers to the failure of the normal relaxation of pelvic floor musclesduring attempted defecation. While not wishing to be bound by anyparticular theory, it is believed that the use calcium channel blockersin accordance with the invention will result in relaxation and/orreduction in tone of the pubococcygeus muscle, or other potentiallyaffected muscles such as the bulbocavernosus, circumvaginal, andperivaginal muscles (in the case of vaginismus) and pelvic floor muscles(in the case of anismus), to relieve the symptoms of these conditionsWhile not wishing to be bound by any particular theory, it is thoughtthat while the calcium channel blockers act most directly on smoothmuscle to reduce tone and trigger point activity, the application ofnifedipine or other calcium channel blockers orally or topically mayreduce the tone, trigger point activity and myofascial restriction ofsmooth muscle found, in around and adjacent to the striated muscles inthe pelvic floor.

For treatment of vaginismus or anismus with topical calcium channelblocker in accordance with the invention, it is generally preferred toapply the calcium channel blocker vaginally for vaginismus, orperianally or intrarectally for anismus. In some embodiments, this canbe accomplished by using a finger or an applicator. Effectiveness can bemeasured by anal manometry, as well as the report of the patient offunctioning of the anus and/or vagina in defecation, sexual activity,sitting and general levels of pain/discomfort.

Calcium channel blockers are a class of drugs that selectively inhibitcalcium movement through calcium channels in cell membranes.Accordingly, calcium channel blockers have a number of physiologicaleffects including, for example, reduction of hypertension.

Since their discovery in 1964, a wide variety of calcium channelblockers have been characterized, any of which can be used in thepresent invention. Calcium channel blockers are typically divided intoseveral classes of compounds, including but are not limited to,dihydropyridines, phenylalkylamines, benzothiapenes, zicotonide, ornon-selective compounds. Exemplary dihydropyridine calcium channelblockers for use in the present invention include, but are not limitedto, amlopidine, aranidipine, azelnidipine, barnidipine, benidipine,cilnidipine, clevidipine, isradipine, efonidipine, felodipine,lacidipone, lercanidipine, manidipine, nicardipine, nifedipine,nilvadipine, nimodipine, nisoldipine, nitrendipine or pranidipine. Insome embodiments, the dihydropyridine calcium channel blocker isnifedipine. Typical phenylalkylamine calcium channel blockers include,but are not limited to varapamil, gallopamil or fendiline. An exemplarybenzothiazepine calcium channel blocker is, for example, diltiazem,while typical non-selective calcium channel blockers include, but arenot limited to, mibefradil, bepridil, flunarizine, fluspirilene orfendiline. In some embodiments, the calcium channel blocker is diltiazemor nifedipine.

L-Arginine (Arg) is a conditionally essential amino acid, naturallyfound in dietary protein. It is converted to nitric oxide (NO) andbronchodilator, a potent vasodilator, by a family of enzymes known asnitric oxide synthase (NOS). NO is an essential molecule that plays arole in a broad range of functions from vascular regulation,neurotransmission, host defense, and cytotoxicity to physiologic controlof airways. Recently, L-arginine has gained popularity as a dietarysupplement, and has been reported to be useful for treatment of analfissures (Gosselink, M. P. et al., Dis. Colon Rectum. 2005 48(4):832-837).

Corticosteroids are known to be useful for, inter alia, treating acuteinflammation. In some embodiments of the methods of the invention asdescribed herein, the pharmaceutical compositions of the inventioninclude, in addition to the therapeutically effective amount of acalcium channel blocker, or L-arginine, or a combination of a calciumchannel blocker and L-arginine, or pharmaceutically acceptable salts,hydrates, solvates and prodrugs thereof, a corticosteroid, for examplecortisone or hydrocortisone. While not wishing to be bound by anyparticular theory, it is believed that the inclusion of thecorticosteroid will assist in alleviating inflammation, and the calciumchannel blocker will promote vasodilation and relaxation of the muscleto which the pharmaceutical composition is administered or applied.Suitable corticosteroids include 21-acetoxypregnenolone, alclometasone,algestone, amcinonide, beclomethasone, betamethasone, budesonide,chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol,corticosterone, cortisone, cortivazol, deflazacort, desonide,desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone diacetonide, and triamcinolone hexacetonide; and apharmaceutically acceptable salts thereof, or phosphate prodrugsthereof, or ester prodrugs thereof.

Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein that areuseful in the treating, reducing, resolving, eliminating, amelioratingand/or preventing the conditions described herein, or one or more of thesymptoms thereof. The pharmaceutical compositions comprise a calciumchannel blocker, or L-arginine, or a combination of a calcium channelblocker and L-arginine, or pharmaceutically acceptable salts, hydrates,solvates and prodrugs thereof in a pharmaceutically acceptable vehicle,carrier, diluent, or excipient, or a mixture thereof.

In one embodiment, provided herein are pharmaceutical compositions inmodified release dosage forms, which comprise a calcium channel blocker,or L-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof, and one or more release controlling excipients asdescribed herein. Suitable modified release dosage vehicles include, butare not limited to, hydrophilic or hydrophobic matrix devices,water-soluble separating layer coatings, enteric coatings, osmoticdevices, multiparticulate devices, and combinations thereof. Thepharmaceutical compositions may also comprise non-release controllingexcipients.

Further provided herein are pharmaceutical compositions in entericcoated dosage forms, which comprise a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof, and one or more release controlling excipients for usein an enteric coated dosage form. The pharmaceutical compositions mayalso comprise non-release controlling excipients.

Additionally provided are pharmaceutical compositions in a dosage formthat has an instant releasing component and at least one delayedreleasing component, and is capable of giving a discontinuous release ofthe active ingredient(s) in the form of at least two consecutive pulsesseparated in time from 0.1 up to 24 hours. The pharmaceuticalcompositions comprise a calcium channel blocker, or L-arginine, or acombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof, and one or more release controlling and non-release controllingexcipients, such as those excipients suitable for a disruptablesemi-permeable membrane and as swellable substances.

In certain embodiments, provided herein are pharmaceutical compositionsin a dosage form for oral administration to a subject, which comprise acalcium channel blocker, or L-arginine, or a combination of a calciumchannel blocker and L-arginine, or pharmaceutically acceptable salts,hydrates, solvates and prodrugs thereof, and one or morepharmaceutically acceptable excipients or carriers, enclosed in anintermediate release layer or matrix material, and an enteric coating.

In one embodiment, the pharmaceutical compositions herein may beprovided in unit-dosage forms or multiple-dosage forms. Unit-dosageforms, as used herein, refer to physically discrete units suitable foradministration to human and animal subjects and packaged individually asis known in the art. Each unit dose contains a predetermined quantity ofthe active ingredient(s) sufficient to produce the desired therapeuticeffect, in association with the required pharmaceutical carriers orexcipients. Examples of unit dosage forms include ampoules, syringesincluding anal syringes, and individually packaged tablets and capsules.Unit-dosage forms may be administered in fractions or multiples thereof.A multiple-dosage form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dosage form. Examples of multiple-dosage forms include vials,bottles of tablets or capsules, and the like.

The calcium channel blocker, or L-arginine, or a combination of acalcium channel blocker and L-arginine, or pharmaceutically acceptablesalts, hydrates, solvates and prodrugs thereof provided herein may beadministered alone, or in combination with one or more other compoundsprovided herein, one or more other active ingredients. Thepharmaceutical compositions that comprise a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof provided herein may be formulated in various dosageforms for oral, parenteral, and topical administration. Thepharmaceutical compositions may also be formulated as modified releasedosage forms, including delayed-, extended-, prolonged-, sustained-,pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Modified orsustained release agents include polymers such as the Eudragit® seriesand cellulose esters. These dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Deliver Technology, Rathbone et al, Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y.,2002; Vol. 126).

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or derivative thereof as described herein.Higher concentrations, up to about 98% by weight of the activeingredient may be included.

Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration.Suitable oral dosage forms include, but are not limited to, tablets,capsules, pills, troches, pellets, granules, bulk powders, effervescentor non-effervescent powders or granules, solutions, emulsions,suspensions, solutions, wafers, sprinkles, elixirs, and syrups. Inaddition to the active ingredient(s), the pharmaceutical compositionsmay contain one or more pharmaceutically acceptable carriers orexcipients, including, but not limited to, binders, fillers, diluents,disintegrants, wetting agents, lubricants, glidants, enteric coatings,film costing agents, modified release agents, coloring agents,dye-migration inhibitors, sweetening agents, and flavoring agents.

Binders or granulators impart cohesiveness to a tablet to ensure thatthe tablet remains intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, ethylcellulose, carboxymethylcellulose, methylcellulose,methyl paraben, polyalkyleneoxides, povidone, polyvinylpyrrolidone(PVP), crospovidones, Veegum, larch arabogalactan, powdered tragacanth,and guar gum; celluloses, such as ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC),hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, suchas AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMCCorp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillersinclude, but are not limited to, talc, calcium carbonate,microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, andmixtures thereof. The binder or filler may be present from about 50 toabout 99% by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, trehalose, lysine, leucine,lecithin, starch, kaolin, sucrose, inositol, cellulose, kaolin,mannitol, sodium chloride, dry starch, and powdered sugar. Certaindiluents, such as mannitol, lactose, sorbitol, sucrose, and inositol,when present in sufficient quantity, can impart properties to somecompressed tablets that permit disintegration in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.Thus, in some preferred embodiments, the active ingredient(s) (i.e., thecalcium channel blocker, or L-arginine, or a combination of a calciumchannel blocker and L-arginine, or pharmaceutically acceptable salts,hydrates, solvates and prodrugs thereof), is administered in apharmaceutical composition which is an immediate release oral dosageform, preferably but not necessarily including an enteric coating. Insome preferred embodiments, the active ingredients(s) are administeredin a pharmaceutical composition which is an extended release oral dosageform, preferably but not necessarily including an enteric coating. Infurther preferred embodiments, the active ingredients are administeredin a pharmaceutical composition which contains both an immediate releasedose and an extended release dose or pulsed release dose of the calciumchannel blocker, preferably but not necessarily also including anenteric coating. Such dual release dosage forms achieve release of aninitial dose of active ingredient, followed late in time by anotherpulsed release, or by a sustained release dose. Methodologies forpreparing such dual release dosage forms are well known in the art.

In some embodiments, the active ingredients are formulated into acontrolled release matrix tablet, which contains one or more polymericmatrix materials that promote the sustained, delayed or pulsed releaseprofile. Non-limiting examples of such polymeric matrix materialsinclude cellulosic materials as described above, and carbomers, forexample those sold by Lubrizol Corporation under the name Carbopol®, forexample Carbopol ® 71G NF, Carbopol® 971P NF and Carbopol® 974P NFpolymers.

Some preferred examples of extended release compositions suitable foruse in the methods and compositions of the invention include, forexample and not limitation, extended release compositions found innifedipine formulations such as Adalat CC®, Procardia XL, Afeditab® CRand Nifedical® XL; and in diltiazem formulations such as Cardizem® CD,Cardizem® LA, Cardizem® SR, Cartia® XT and Dilacor® XR.

Oral administration of the calcium channel blocker, or L-arginine, orcombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof, with or without an anti-inflammatory active such as cortisoneor cortisol, is particularly effective for patients that have conditionsthat limit direct access to the target muscle, e.g., patients thatsuffer from, for example and not limitation, anal cancer and patientswho have had a colostomy. The sphincters of these patients are typicallysewn shut, thus limiting the direct rectal access to the pelvic floormuscles. It should be noted that while oral administration in accordancewith the methods of the invention is particularly indicated for suchpatients, oral administration is also a particularly convenient route ofadministration for all patients, including those with direct access tothe target muscle.

In some embodiments, the invention provides pharmaceutical compositionsfor oral administration, and particularly extended release oralformulations, for use in treating the conditions and disorders describedherein, including for example pelvic pain disorders, such as prostatitiscategory IIIA and/or IIIB in a male patient, chronic pelvic pain, pelvicfloor muscles with trigger points or areas of myofascial restriction,chronic pelvic pain syndrome, pelvic floor myalgia, pelvic floordysfunction, interstitial cystitis, levator ani syndrome, coccygodynia,prostatodynia, prostadynia, piriformis syndrome, anal sphincter pain,bowel movement pain, post bowel movement pain, ejaculatory pain,ejaculatory discomfort, post ejaculatory pain, sitting pain, rectalpain, tailbone pain, urinary frequency, urinary urgency, urinaryhesitancy, perineal pain, penile pain, vaginismus, anismus, sexualdysfunction, reduced level of ejaculate or reduced penile erection,nonbacterial prostatitis, slow urinary flow, reduced urinary flow, postejaculatory discomfort, urinary or urethral sphincter spasms, posturinary pain, rectal sphincter spasms, proctalgia fugax, myofascial painin muscle tissue of a patient who has one or more trigger points in themuscle tissue, and the pain/sensitivity of pelvic floor muscle triggerpoints and specific areas of myofascial restriction detected uponpalpation in a patient; wherein the composition comprises a calciumchannel blocker, for example nifedipine or diltiazem. In someembodiments, the calcium channel blocker is nifedipine, which is presentin an amount of from 1-90 mg. In some further embodiments, the calciumchannel blocker is nifedipine, which is present in an amount of 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 mg of nifedipine;preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85 or 90 mg of nifedipine, or 5, 15, 25, 35, 40, 45, 50, 55, 65, 70,75, 80, 85 or 90 mg of nifedipine. In some preferred embodiments, thepharmaceutical composition is an extended release composition.

In some embodiments, the methods of the invention include theadministration of an enterically coated extended release dosage formcomprising calcium channel blocker as described herein, for examplenifedipine or diltiazem, wherein the calcium channel blocker is embeddedwithin, or encapsulated by, one or more mucoadhesive polymers.Preferably, the mucoadhesive polymer(s) has extended releaseproperties—i.e., it effects a delayed release of active from thepolymer—or the dosage form additionally contains one or moredelay-released agents, as described below, to effect a delayed releaseof the active(s). In some such embodiments the enteric coating delaysrelease of the mucoadhesive polymer containing the active ingredient(s)until the dosage form is in the large intestine. While not wishing to bebound by a particular theory, it is believed that upon release orshortly thereafter, the mucoadhesive polymer will adhere to the wall ofthe large intestine, and the active ingredients will then be releasedslowly to the local environment, where it will both exert its effectlocally, and also diffuse into the blood. Thus, it is thus believed thatthe release and distribution profile of the dosage form will displayboth systemic and local effects. It is believed that such a dual effectwould aid in lessening the spasticity of the affected muscles, forexample colon muscles and pelvic floor muscles, and thus affordsignificant benefits in treatment of the conditions described herein,including anal fissures, pelvic pain disorders, chronic pelvic pain,pelvic floor muscles with trigger points or areas of myofascialrestriction, chronic pelvic pain syndrome, pelvic floor myalgia, pelvicfloor dysfunction, interstitial cystitis, levator ani syndrome,coccygodynia, prostatodynia, prostadynia, piriformis syndrome, analsphincter pain, bowel movement pain, post bowel movement pain,ejaculatory pain, ejaculatory discomfort, post ejaculatory pain, sittingpain, rectal pain, tailbone pain, urinary frequency, urinary urgency,urinary hesitancy, perineal pain, penile pain, vaginismus, anismus,sexual dysfunction, reduced level of ejaculate or reduced penileerection, nonbacterial prostatitis, slow urinary flow, reduced urinaryflow, post ejaculatory discomfort, urinary or urethral sphincter spasms,post urinary pain, rectal sphincter spasms, proctalgia fugax, myofascialpain in muscle tissue of a patient who has one or more trigger points inthe muscle tissue, and the pain/sensitivity of pelvic floor muscletrigger points and specific areas of myofascial restriction detectedupon palpation in a patient.

Suitable mucoadhesive polymers include, but are not limited to, natural,semi-synthetic and synthetic polymers, hydrophilic polymers, hydrogels,protein polymers (proteins and polypeptides), carbohydrate polymers(polysaccharides), glycoproteins, copolymers including block copolymers,and any of the foregoing that have been further modified to includethiol or disulfide functional groups (thiolated polymers). Suchthiolated polymers may include modifications of natural, semi-syntheticor synthetic polymers that incorporate cysteine, homocysteine,thioglycolic acid, thioethylamidine, iminothiolane,isonicotinamide-disulfide, pyridoxine-dilsulfide, or other thiol ordisulfide functional groups. Natural polymers include, but are notlimited to, alginates, agarose, pectins, chitosans, mucins, gelatin,gums (e.g., guar gum, karaya gum, xanthan gum, Arabic gum, gellan gum,carrageenan), retene, tragacanth, hyaluronan, starches and celluloses.Semi-synthetic polymers include any natural polymers modified bychemical or physical means. Further suitable mucoadhesive polymersinclude those that are modified to incorporate specific bacterialfimbrial proteins, such as E. Coli antigen K99. Specific nonlimitingexamples of mucoadhesive polymers embraced by the current inventioninclude cellulose, microcrystalline cellulose, modified celluloses(including hydroxypropyl methylcellulose, hypromellose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, sodiumcarboxymethyl cellulose and ethyl cellulose), poly(vinylpolypyrrolidone)(Crospovidone), poly(vinylpyrrolidone) (Povidone), polydextrose,polyvinyl alcohol, polysorbate, polyethylene glycol, polyethylene oxide(including Polyox WSR), polyacrylic acid, polypropylene glycol,polyethylene glycol/polypropylene glycol block copolymers (such asPoloxamers, including Poloxamer 407P and Poloxamer 188P), cross-linkedpolyacrylates (such as Carbopols, including Carbopol 934P, Carbopol 940,Carbopol 971P, Carbopol 974P, Carbopol 981), cyclodextrins (includingalpha-, beta- or gamma-cyclodextrin, and modified cyclodextrins such ashydroxypropyl-beta-cyclodextrin), dextrans, dendrimers, polycarbophil,poly(dimethyl siloxane), poly(hydroxyethyl methacrylate),cyanoacrylates, hyaluronic acid, polyvinyl ethers, wheat germagglutinin, and natural-synthetic polymer complexes (such aspoly(ethylene glycol)-alginate complex). Further examples are disclosedin Shaikh, et al., Mucoadhesive Drug Delivery Systems, J. Pharm.Bioallied Sci., 2011 January-March, 3(1):89-100, and the referencescited within, which is incorporated herein by reference in its entirety.

In some embodiments of the methods of the invention, an oral dose of acalcium channel blocker, for example nifedipine or diltiazem, isadministered in conjunction with the protocol involving manual ordevice-assisted placement of a topical pharmaceutical composition, forexample by use of a trigger-point wand, as discussed above. While notwishing to be bound by a particular theory, it is believed that the oralcalcium channel blocker facilitates the usefulness of the protocol byrelaxing the anal sphincter, and thus affording easier, less painful andmore effective use of the protocol.

Parenteral Administration

The present invention also includes parenteral administration, inparticular by injection, preferably directly into muscle of a patient,more preferably directly into to one or more specific trigger points inthe muscle, for example and not limitation, the pelvic floor muscle, orexternal trigger pointed muscle.

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, preferably but notnecessarily for local administration. Parenteral administration, as usedherein, includes intramuscular and subcutaneous administration, andincludes the administration of long-acting or depot intramuscular drugformulations.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

Pharmaceutical compositions suitable for injection can be prepared inconventional forms, either as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions. The compositions also can contain one or moreexcipients such as, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents, stabilizers,solubility enhancers, and other such agents, such as for example, sodiumacetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.Injectable pharmaceutical compositions also can other components knownto be useful in injectable formulations, and in particular intramuscularinjection formulations, for example isotonic agents such as sodiumchloride and dextrose, buffers such as phosphate and citrate;antioxidants such as sodium bisulfate; local anesthetics such aslidocaine and procaine hydrochloride; suspending and dispersing agentssuch as sodium carboxymethylcelluose, hydroxypropyl methylcellulose andpolyvinylpyrrolidone; and emulsifying agents such as Polysorbate 80(Tween® 80).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride,benzethonium chloride, methyl- and propylparabens, and sorbic acid.Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin,hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, andsulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semisolid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

Lyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures, or reconstituted and formulatedas solids or gels, also find use with the present invention. Thesterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a derivative thereof, in a suitable solvent. Thesolvent may contain an excipient which improves the stability or otherpharmacological component of the powder or reconstituted solution,prepared from the powder. Excipients that may be used include, but arenot limited to, an antioxidant, a buffer and a bulking agent. In someembodiments, the excipient is selected from dextrose, sorbital,fructose, corn syrup, xylitol, glycerin, glucose, sucrose and othersuitable agent. The solvent may contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to those ofskill in the art at, at about neutral pH. Subsequent sterile filtrationof the solution followed by lyophilization under standard conditionsknown to those of skill in the art provides the desired formulation. Insome embodiments, the resulting solution will be apportioned into vialsfor lyophilization. Each vial will contain a single dosage or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration as describedabove. For reconstitution, the lyophilized powder is added to sterilewater or other suitable carrier. The precise amount depends upon theselected compound. Such amount can be empirically determined.

Generally, the concentration of active agent is adjusted so that aninjection provides an effective amount to produce the desiredpharmacological effect in the affected muscle. Injectables in accordancewith the invention are preferably designed for local administration, andpreferably avoid systemic administration of the active agent. The exactdose depends on the specific condition of the patient or animal as isknown in the art.

Topical Administration

The topical pharmaceutical compositions provided herein may beadministered to the skin, orifices, or mucosa. The topicaladministration, as used herein, includes (intra)dermal, transdermal,vaginal, uretheral, and rectal and intrarectal administration. Topicalformulations may include from 0.5 to 5% calcium channel blocker, forexample 0.5 to 3% nifedipine.

In some embodiments, administration of the active ingredients of theinvention differs from current treatment of open wounds such as analfissures. For example, topical treatment of anal fissures typicallyinvolves administration of a topical formulation to an area between theanal opening and the first 1 cm of the anal canal (see, for example,Golfam, F., et al., supra), and in some cases to approximately the first1 to 3.5 inches of the anal canal. In contrast, the trigger pointstypically identified in accordance with the conditions identified hereinare typically in the internal and external anal sphincter and located inthe muscles of the pelvic floor as illustrated and described in the6^(th) edition of Wise's book, A Headache in the Pelvis, describedsupra. While not wishing to be bound by any particular theory, it isbelieved that tissue and environmental differences between the two sitescan influence the permeability and effectiveness of the appliedcomposition.

In addition, the present invention also provides compositions andmethods for treatment of anal fissures, and alleviation of symptoms ofanal fissures, which in one embodiment comprises perianal or intrarectaladministration of a topical composition comprising the activeingredients according to the present invention, and in a furtherembodiment comprises oral administration of the active ingredientsaccording to the present invention, each to a patient in need thereof.

In some preferred embodiments, the methods of the invention areperformed using topical pharmaceutical compositions as described herein.For topical compositions in accordance with the invention,administration is preferably local. In some preferred embodiments, atopical pharmaceutical composition is prepared for local administrationand specifically avoids systemic administration. The resulting mixturemay be a solution, suspension, emulsions or the like and are formulatedas creams, gels, ointments, emulsions, solutions, elixirs, lotions,suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays,suppositories, bandages, dermal patches or any other formulationssuitable for topical administration. The mixture may include glycerin ora poloxamer, paraffin, conventional ointment formulations or any othersuitable material. The topical pharmaceutical composition may include alocal anesthetic such as, for example, benzocaine, chloroprocaine,cocaine, cyclomethycaine, lidocaine, dimethococaine, piperocaine,procaine, novocaine, procaine, tetracaine, articane, bupivacaine,cinchocaine, dibucaine, etidocaine, levobupivicanine, lignocaine,mepivocaine, prilocaine, ropivacaine, trimecaine, eugenol, menthol,saxitoxin or tetrodoxin. In some embodiments, the local anesthetic islidocaine.

In still other embodiments, the topical pharmaceutical composition maycontain 1.5% lidocaine. In some embodiments, a topical pharmaceuticalcomposition includes 2% diltiazem, 1.5% lidocaine, in a base of 30%poloxamer 407 and glycerin or in a paraffin or ointment base of anytypical kind. In some embodiments, a topical pharmaceutical compositionincludes 0.3%-3% nifedipine, in 30% poloxamer 407 and/or in a paraffinor ointment base of any typical kind. In some embodiments, a topicalpharmaceutical composition includes 0.5%-1% nifedipine, in a base of anytypical kind.

In some embodiments, the topical pharmaceutical composition is appliedby use of a protocol involving manual or device-assisted placement of atopical pharmaceutical composition, as discussed below.

In some embodiments, the topical pharmaceutical composition is appliedby placing the medication on one's gloved finger to then be insertedinside the sphincter or vagina as far as a finger can reach to placeswhere trigger points reside that the patient has been taught to locateand to apply the calcium channel blocker topically. In some embodiments,the topical pharmaceutical composition is applied by placing themedication on the tip of a device to then be inserted inside thesphincter or vagina. Examples of devices that are suitable for thispurpose are internal trigger point wands (see, e.g. U.S. Pat. Nos.8,337,435 and 8,224,464, each of which is incorporated herein byreference in its entirety for all purposes). In some embodiments, thetopical pharmaceutical composition is applied by the use of a drugapplicator sleeve and in combination with a device such as, for example,a syringe, probe or pressure applicator such as an internal triggerpoint wand, as described below. In some such embodiments, the calciumchannel blocker, L-arginine or combination thereof is administeredthrough the use of a drug applicator sleeve that surrounds the syringe,probe or pressure applicator.

In some preferred embodiments, the topical pharmaceutical composition isapplied to identified trigger points as described herein. Procedures foridentifying such trigger points are known, and within the ambit of thisof skill in the art. Typically, a skilled practitioner will take ahistory of a patient complaining of pain and will know the approximatenumber and location of trigger points associated with the symptom thatis being complained of. The skilled practitioner who treats pelvic painwill then palpate tissue both outside and inside of the pelvic floor tosee if the typical indications of a trigger point (jump sign uponpalpation, twitch response felt by practitioner upon palpation,perception of a taut band of muscle fiber that is exquisitely tender andrefers pain and typically recreates the symptom of the patient). Theforegoing procedures are also described in Travell & Simons, MyofascialPain and Dysfunction, The Trigger Point Manual (Volumes I and II),2^(nd) Ed., J. Butler, Ed., Williams & Wilkins; 1983. See also Wise, D.T. et al., A Headache in the Pelvis: A new understanding and treatmentfor chronic pelvic pain syndromes, 6^(th) ed.; ISBN 978-0-9727755-5-7;National Center for Pelvic Pain Research, PO Box 54, Occidental, Calif.95465; pp. 104-110: 265-277; 379-387: Anderson et al., PainfulMyofascial Trigger Points and Pain Sites in Men With ChronicProstatitis/Chronic Pelvic Pain Syndrome, J Urol 182 (6): 2753-8, eachof which is incorporated by reference in its entirety.

Preferably, the topical pharmaceutical composition is a cream orointment, which can be, but is not necessarily, sticky and thickeningwith body heat—i.e., will tend to stick to the tissue to which it isapplied. While not wishing to be bound by any particular theory, it isbelieved that a sticky ointment might promote local administration andefficacy of the active ingredient(s) by preventing migration of theointment to other tissues. Moreover, it is preferable that the topicalcomposition possesses a suitable balance between gel and liquidproperties. It has been found that such properties are successfullyimparted by inclusion of a nonionic surfactant with glycerin or in aparaffin or ointment base of any typical kind. In one preferredembodiment, the topical pharmaceutical composition comprises apoloxamer, for example poloxamer 407®. While not wishing to be bound byany particular theory, it is believed that poloxamers, and in particularpoloxamer 407® are advantageous in that the combination of the poloxamerplus calcium channel blocker, for example and not limitation nifedipineor diltiazem, and/or L-arginine, forms a unique composition that hasbioadhesive and healing properties. It also is believed that thecomposition has the beneficial property of increasing in viscosity orsolidity as its temperature increases. These properties may bebeneficial in promoting the local administration of the activeingredient(s), and resisting systemic absorption. Indeed, in themethodology discussed in the Wise publications mentioned above, patientsare taught the anatomy of pelvic floor, and the application of pressurein specific areas in the pelvic floor to relieve trigger point activity,either manually or using an applicator such as a syringe or an internaltrigger point wand as described in, e.g. U.S. Pat. Nos. 8,337,435 and8,224,464, each of which is incorporated herein by reference in itsentirety for all purposes. In some embodiments of the present invention,the patient uses the wand to deliver a bioadhesive product of theinvention; e.g., a composition comprising poloxamer 407® and a calciumchannel blocker, L-arginine, or both, to the specific area. It isbelieved that the bioadhesive properties of the composition retardsmigration of the composition, thus promoting the retention of activeingredients in the specific place it is most effective, and thus alsominimizing systemic absorption.

Thus, in some embodiments, the pharmaceutical compositions of theinvention can include one or more mucoadhesive polymers, which serve toprolong the residence time of the dosage form through various mucosalroutes in drug delivery applications, and enhance bioavailability of theactive ingredient(s). Examples of mucoadhesive polymers include, withoutlimitation, the cellulose derivatives discussed above, poly(acrylicacids) such as Carbopol® polymers, also described above, and Gantrez®copolymers such as poly(methylvinylether/maleic anhydride). Furtherexamples are disclosed in Shaikh, et al., Mucoadhesive Drug DeliverySystems, J. Pharm. Bioallied Sci., 2011 January-March, 3(1):89-100, andthe references cited within.

Preferred nonionic surfactants for topical compositions of the inventioninclude, without limitation, polymers and co-polymers of ethylene glycoland propylene glycol, e.g., poloxamers, i.e., nonionic triblockcopolymers composed of a central hydrophobic chain of polyoxypropylene(poly(propylene oxide)) flanked by two hydrophilic chains ofpolyoxyethylene (poly(ethylene oxide)). The approximate lengths of thetwo PEG blocks is, in some embodiments, an average of about 50-150repeat units, e.g., about 100 repeat units while the approximate lengthof the propylene glycol block is an average of about 25-75 repeatunties, e.g., about 50-60 repeat units. In one preferred embodiment, thepoloxamer is poloxamer 407, also known by the BASF trade name PluronicF127, e.g., in an amount of from 0.3% to 50% by weight; or from 20% to40% by weight, or from 25% to 35% by weight, or about 30% by weight ofthe formulation.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration, preferablybut not necessarily for local effect, including emulsions, solutions,suspensions, creams, gels, hydrogels, ointments, dusting powders,dressings, elixirs, lotions, suspensions, tinctures, pastes, foams,films, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches. The topical formulation of the pharmaceutical compositionsprovided herein may also comprise liposomes, micelles, microspheres,nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon bases, including such as lard, benzoinatedlard, olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption bases, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable bases,such as hydrophilic ointment; water-soluble ointment bases, includingpolyethylene glycols of varying molecular weight; emulsion bases, eitherwater-in-oil (W/O) emulsions or oil-in-water (OAV) emulsions, includingcetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see,Remington: The Science and Practice of Pharmacy, supra). These vehiclesare emollient but generally require addition of antioxidants andpreservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include vehicles, such asstiffening agents, which produce a melting point in the proximity ofbody temperature, when formulated with the pharmaceutical compositionsprovided herein; and antioxidants as described herein, includingbisulfite and sodium metabisulfite. Suitable vehicles include, but arenot limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax,and appropriate mixtures of mono-, di- and triglycerides of fatty acids,hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate,polyacrylic acid; glycerinated gelatin. Combinations of the variousvehicles may be used. Rectal and vaginal suppositories may be preparedby the compressed method or molding. The typical weight of a rectal andvaginal suppository is about 2 to 3 g.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile- orpulsed-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NI);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In another embodiment, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device include, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinylchloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethyleneterephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers,hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

Controlled Release Devices Osmotic

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”include, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-tolunesulfonic acid, succinic acid, and tartaric acid; urea; andmixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MannogemeEZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

The semipermeable membrane may also be a hydrophobic microporousmembrane, wherein the pores are substantially filled with a gas and arenot wetted by the aqueous medium but are permeable to water vapor, asdisclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vaporpermeable membrane are typically composed of hydrophobic polymers suchas polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients asdescribed herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients. See,U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-releasedosage forms can be prepared according to conventional methods andtechniques known to those skilled in the art, including directcompression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients.

Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to 1 mm in diameter. Such multiparticulatesmay be made by the processes know to those skilled in the art, includingwet- and dry-granulation, extrusion/spheronization, roller-compaction,melt-congealing, and by spray-coating seed cores. See, for example,Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; andPharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

In some topical embodiments, a controlled release system can be placedin proximity of the therapeutic target, i.e., thus requiring only afraction of the systemic dose (see, e.g., Goodson, Medical Applicationsof Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments,a controlled release device, or a topical composition as described belowwhich contains matrix material which effects a controlled or extendedrelease of the active ingredients is introduced into a subject inproximity of the site of a pelvic floor muscle trigger point and/orspecific areas of myofascial restriction detected upon palpation in apatient.

The active ingredient can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active ingredientcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject. Othercontrolled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)), incorporated herein by reference.

Dosages

The compositions provided herein contain therapeutically effectiveamounts of one or more of the compounds provided herein that are usefulin the prevention, treatment, or amelioration of one or more of thesymptoms of diseases or disorders described herein and a vehicle.Vehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration, preferablytopically, orally or via injection. In addition, the compounds may beformulated as the sole active ingredient in the composition or may becombined with other active ingredients.

The active compound is included in the vehicle in an amount sufficientto exert a therapeutically useful effect in the absence of undesirableside effects on the patient treated. The therapeutically effectiveconcentration may be predicted empirically by testing the compounds inin vitro and in vivo systems well known to those of skill in the art andthen extrapolated there from for dosages for humans. Human doses arethen typically fine-tuned in clinical trials and titrated to response.

The concentration of active compound in the composition will depend onabsorption, inactivation and excretion rates of the active compound, thephysicochemical characteristics of the compound, the dosage schedule,and amount administered as well as other factors known to those of skillin the art. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of diseases or disorders asdescribed herein.

In some embodiments, a therapeutically effective dosage should be fromabout 0.0001 mg to about 90 mg of each active ingredient (i.e., one ormore of calcium channel blocker, L-arginine and/or corticosteroid) perkilogram of body weight per day, delivered topically, orally or by localinjection as descried herein. In some embodiments, the calcium channelblocker is administered at a dosage of up to 120 mg/day, for example 90mg/day, 85 mg/day, 80 mg/day, 75 mg/day, 70 mg/day, 65 mg/day, 60mg/day, 55 mg/day, 50 mg/day, 45 mg/day, 40 mg/day, 35 mg/day, 30mg/day, 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 5 mg/day, 2 mg/dayor 1 mg/day.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from vehicle or carrier maybe prepared. Methods for preparation of these compositions are known tothose skilled in the art. The contemplated compositions may contain0.001%-100% active ingredient, in one embodiment 1%-3%, in anotherembodiment 2% and in still another embodiment, 1% to 3%. Actual methodsof preparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 orlater editions thereof.

Oral Dosage

The oral dosage forms of the invention that contain calcium channelblockers, for example and not limitation nifedipine or diltiazem, willtypically contain a lower dose of calcium channel blockers than istypically administered for use in indications such as hypertension.Thus, dosages for calcium channel blockers used in accordance with themethods and compositions of the present invention are typically lessthan about 95% of the dosages used for other presently approvedindications.

For example, nifedipine dosages in accordance with the pharmaceuticalcompositions and methods of the invention can be from are typically upto about 120 mg/day, for example from 10 mg/day to about 90 mg/day, forexample from 20 mg/day to about 90 mg/day, for example 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 95, 100, 110, 115 or 120mg/day; or for example 5, 15, 25, 35, 40, 45, 50, 55, 65, 70, 75, 80,85, 90, 95, 100, 110, 115 or 120 mg/day; for example 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 mg/day.

In some preferred embodiments, the daily dose is administered once perday in an extended release composition.

In other embodiments, the daily dose is administered in smallerincrements given multiple times per day, for example twice or threetimes per day, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39 or 40 mg, taken 3 times daily; or 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44 or 45 mg, taken 2 times daily; or any combination of theabove.

Similarly, diltiazem dosages in accordance with the pharmaceuticalcompositions and methods of the invention are typically less than 180mg/day, for example 170 mg/day, 160 mg/day, 150 mg/day, 140 mg/day, 130mg/day, 120 mg/day, 110 mg/day, 100 mg/day, 90 mg/day, 80 mg/day, 70mg/day, 60 mg/day, 50 mg/day, 40 mg/day, 30 mg/day, 20 mg/day, 10 mg/dayor 5 mg/day, taken for example and not limitation at smaller dosagesseveral times per day, for example 2 or 3 times per day, in amounts thatcombined equal the daily values above. For extended-release dosageforms, diltiazem dosages in accordance with the pharmaceuticalcompositions and methods of the invention are typically less than 180mg, taken once daily, for example and not limitation 1-170 mg, takenonce daily; for example 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg,110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg,10 mg or 5 mg, each taken once daily.

Topical Dosages

In some embodiments, the topical formulations of the present inventionemploy concentrations of calcium channel blocker and/or L-arginine thatare therapeutically effective to treat the pelvic pain conditionsdescribed herein. Generally, the concentration of calcium channelblocker and/or L-arginine required for treatment by topical applicationto pelvic pain trigger points in accordance with the present inventionare higher than for topical treatment of other conditions, for exampleopen wounds such as anal fissures.

For example, in some embodiments, preferred concentrations and dosagesof calcium channel blockers and/or L-arginine include a) for a topicalformulation containing 0.5% active: 3 mg/dose, 6 mg for two doses, and 9mg for 3 doses; b) for a topical formulation containing 1% active: 6mg/dose, 12 mg for two doses, and 18 mg for 3 doses; c) for a topicalformulation containing 2% active: 12 mg/dose, 24 mg for two doses, and36 mg for 3 doses; and d) for a topical formulation containing 3%active: 18 mg/dose, 36 mg for two doses, and 54 mg for 3 doses.

The compounds or derivatives may be packaged as articles of manufacturecontaining packaging material, a compound or derivative thereof providedherein, which is effective for treatment, prevention or amelioration ofone or more symptoms of the diseases or disorders, supra, within thepackaging material, and a label that indicates that the compound orcomposition or derivative thereof, is used for the treatment, preventionor amelioration of one or more symptoms of the diseases or disorders,supra.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging products are well known tothose of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907,5,052,558 and 5,033,252. Examples of packaging materials include, butare not limited to, blister packs, bottles, tubes, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.A wide array of formulations of the compounds and compositions providedherein are contemplated as are a variety of treatments for any diseaseor disorder described herein.

In accordance with another aspect of the disclosure herein, delivery ofa topical pharmaceutical composition to a treatment site within therectal cavity or the vaginal cavity of a human patient can be aided byan apparatus that includes an applicator member and a drug deliverydevice defined in part by a tubular member. The topical pharmaceuticalcomposition is located in the tubular member. The tubular member is thenplaced partially into the rectal cavity or the vaginal cavity of thehuman patient. The drug delivery device can be used with an applicatormember. The applicator member is adapted to apply the topicalpharmaceutical composition to the treatment site. At least one of thedrug delivery device or the applicator member can also be adapted toapply pressure to the treatment site, thereby allowing pres sure-basedtherapies such as trigger point release to be performed at the sametime. As the applicator member is guided through the sleeve and thusinto the rectal cavity or the vaginal cavity of the human patient, thetopical pharmaceutical composition is moved out of the sleeve, and isdirected to the treatment site by the applicator member. Inimplementations where the applicator member is a pressure applicator,pressure can be applied to the treatment site by the pressure applicatorat the time of delivery of the topical pharmaceutical composition to thetreatment site.

FIGS. 1A-1B show a delivery device 100 according to a first example andan applicator member 20.

The device 100 includes tubular member 110 having a hollow interior thatextends from a first open end 112 to a second open end 114. A topicalpharmaceutical composition 102 is disposed within the hollow interior ofthe tubular member 110.

In the illustrated example, the first open end 112 of the tubular member110 is directed toward a treatment site 10, which can be a portion ofthe body of a human patient, such as an internal tissue of the rectalcavity or the vaginal cavity of the human patient. During use of thedevice 100, the tubular member is partially inserted into the rectalcavity or the vaginal cavity of the patient, such that the first openend 112 of the tubular member 110, is disposed within the patient'sbody, and the second open end 114 of the tubular member 110 is locatedoutside of the patient's body.

The applicator member is adapted to be inserted through the hollowinterior of the tubular member 110 of the device 100. The applicatormember 20 can be an elongate member that has a tip 22 at one endthereof. The tip 22 is shaped and sized complementarily to thecross-sectional shape and size of the hollow interior of the tubularmember 110. A maximum width or diameter can be approximately equal to orslightly smaller than an inside width or diameter of the hollow interiorof the tubular member 110. In the illustrated example, the tip 22 isshaped as a partial sphere, and the remainder of the applicator memberis substantially cylindrical. It should be understood, however, thatother structural configurations can be utilized.

Initially, the tubular member 110 of the device 100 is insertedpartially into the rectal cavity or the vaginal cavity of the humanpatient, via the patient's anal sphincter or vaginal opening. The firstopen end 112 of the tubular member 110 is located inside the rectalcavity or the vaginal cavity of the human patient, and is directedtoward the treatment site 10. The tip 22 of the applicator member 20 isinserted into the hollow interior of the tubular member 110 through thesecond open end 114 of the tubular member 110 to define a first position(FIG. 1A) of the applicator member 20 with respect to the tubular member110 of the device 100. The applicator member 20 is then moved throughthe hollow interior of the tubular member 110 toward the first open end112 of the tubular member 110, until the tip 22 extends partially out ofthe first open end 112 of the tubular member 110 to define a secondposition (FIG. 1B). As the applicator member 20 moves through thetubular member 110, at least a portion of the topical pharmaceuticalcomposition 102 is pushed out of the tubular member 110 by theapplicator member 20, such that the topical pharmaceutical compositionexits the tubular member via the first open end 112 thereof, and isdirected to the treatment site 10 by the tip of the applicator member20. Optionally, the tip 22 of the applicator member 20 can then beengaged with the treatment site 10 for applying pressure to thetreatment site 10.

FIG. 2 shows a drug delivery device 200 according to a second example.The device 200 is similar to the device 100 except as noted. The device200 includes a tubular member 210 having a hollow interior with atopical pharmaceutical composition 202 disposed therein. A first sealmember 220 is disposed at a first end of the tubular member 210 and asecond seal member 230 is disposed at a second end of the tubular member210. The first and second seal members 220, 230 are removable membersmade of a material such as a film or a foil that is adhered to thetubular member 210 to seal the hollow interior of the device 200 priorto use. The first and second seal members are removed prior to use, anduse of the device 200 is otherwise as described with respect to thedevice 100.

FIG. 3 shows a drug delivery device 300 according to a second example.The device 300 is similar to the device 100 except as noted. The device300 includes a tubular member 310 having a hollow interior with atopical pharmaceutical composition 302 disposed therein. A firstfrangible member 320 is disposed within the hollow interior of thetubular member 310 and a second frangible member 330 is disposed withinthe hollow interior of the tubular member 310. The first and secondfrangible members 320, 330 are initially located such that the topicalpharmaceutical composition 302 is disposed between them to seal andprotect the topical pharmaceutical composition 302, and, are puncturedduring movement of an applicator member through the tubular member 310,thus releasing the topical pharmaceutical composition 302. Use of thedevice 300 is otherwise as described with respect to the device 100.

FIG. 4 shows a drug delivery device 400 according to a second example.The device 400 is similar to the device 100 except as noted. The device400 includes a tubular member 410 having a hollow interior with atopical pharmaceutical composition 402 disposed therein. A firstencapsulating material layer 420 is disposed within the hollow interiorof the tubular member 410 and a second encapsulating material layer 430is disposed within the hollow interior of the tubular member 410. Thefirst and second encapsulating material layers 420, 430 can be anon-toxic biocompatible material that can be absorbed or passed by thepatient's body, but are able to seal and protect the topicalpharmaceutical composition 402 within the tubular member 410 at dry,room temperature conditions. As one example, the encapsulating materialcan be wax. As another example, the encapsulating material can bepetroleum jelly. The first and second encapsulating material layers 420,430 are initially located such that the topical pharmaceuticalcomposition 402 is disposed between them to seal and protect the topicalpharmaceutical composition 402, and, are pushed out of the tubularmember 410 during movement of an applicator member through the tubularmember 410, thus releasing the topical pharmaceutical composition 402.Use of the device 400 is otherwise as described with respect to thedevice 100.

FIGS. 5A-5B show a drug delivery device 500 according to a fifthexample. The device 500 is similar to the device 100 except as noted,and includes a tubular member 510 having a topical pharmaceuticalcomposition 502 disposed within a hollow interior thereof. The tubularmember 510 extends from a first end 512, which is disposed within thepatient's body and directed toward the treatment site 10 when in use,and a second end 514, which is an open end of the tubular member 510that is disposed outside of the patient's body when in use. The firstend 512 of the tubular member 510 has an approximately semi-sphericalconfiguration that is defined by a plurality of segments 520. Theplurality of segments 520 are each approximately wedge shaped portionsof the semi-spherical configuration that are arrayed radially. Radiallyadjacent segments from the plurality of segments 520 are separated fromone another by longitudinally extending slits. All of the segments meetone another at a location along the longitudinal axis of the tubularmember 510 at the first end 512.

In a first position (FIG. 5A), the tip 22 of the applicator member 20 isdisposed within the hollow interior of the tubular member 510 of thedevice 500, at a location that is adjacent to the second end 514 of thetubular member 510. As the tip 22 is moved through the tubular member510 toward the first end 512, the tip 22 contacts the topicalpharmaceutical composition 602 and displaces it within the tubularmember 510, such that the topical pharmaceutical composition 502 ispushed through the tubular member 510 in response to movement of the tip22 of the applicator member 20. When the tip 22 reaches the plurality ofsegments 520 at the first end 512 of the tubular member 510, eachsegment from the plurality of segments 520 moves radially outward, suchas by flexing or deforming, in response to the pressure applied byengagement of the tip 22 and/or the topical pharmaceutical composition502 with respect to the plurality of segments 520. This causes theplurality of segments 520 to move from a closed position in which theydefine the substantially semi-spherical configuration, to an openposition (FIG. 5B), wherein an opening of a size sufficient to allowpassage of the tip 22 of the applicator member 20 is defined between theplurality of segments 520 along the longitudinal axis of the tubularmember 510. This allows the tip 22 to pass out of the device 500 at thefirst end thereof while directing the topical pharmaceutical composition502 out of the device 500 to the treatment site 10. Optionally, the tip22 of the applicator member 20 can then be engaged with the treatmentsite 10 for applying pressure to the treatment site 10.

FIGS. 6A-6B show a drug delivery device 600 according to a sixthexample. The device 600 is similar to the device 100 except as noted,and includes a tubular member 610 having a topical pharmaceuticalcomposition 602 disposed within a hollow interior thereof. The tubularmember 610 extends from a first end 612, which is disposed within thepatient's body and directed toward the treatment site 10 when in use,and a second end 614, which is an open end of the tubular member 610that is disposed outside of the patient's body when in use. The firstend 612 of the tubular member 612 has an approximately semi-sphericalshape. One or more apertures extend through the wall of the tubularmember 610 at the first end 612.

In a first position (FIG. 6A), the tip 22 of the applicator member 20 isdisposed within the hollow interior of the tubular member 610 of thedevice 600, at a location that is adjacent to the second end 614 of thetubular member 610. As the tip 22 is moved through the tubular member610 toward the first end 612, the tip 22 contacts the topicalpharmaceutical composition 602 and displaces it within the tubularmember 610, such that the topical preparation is pushed through thetubular member 610 in response to movement of the tip 22 of theapplicator member 20. When the tip 22 reaches the first end 612 of thetubular member 610, the topical pharmaceutical composition 602 is forcedthrough the apertures 620 to the exterior of the device 600 and towardthe treatment site 10 (FIG. 6B). Optionally, the first end 612 of thedevice 600 can then be engaged with the treatment site 10 for applyingpressure to the treatment site 10, in response to forces applied to thedevice 600 by the tip 22 of the applicator member 20.

FIGS. 7A-7B show a drug delivery device 700 according to a seventhexample. The device 700 is similar to the device 100 except as noted,and includes a tubular member 710 having a topical pharmaceuticalcomposition 702 disposed within a hollow interior thereof. The tubularmember 710 extends from a first end 712, which is an open end of thetubular member 710 that is disposed within the patient's body anddirected toward the treatment site 10 when in use, to a second end 714,which is an open end of the tubular member 710 that is disposed outsideof the patient's body when in use. A stop surface is provided on thedevice 700 at the second end 714 and is configured to restrain furtherinsertion of the device 700 with respect to the patient. The stop canbe, for example, a flange 720 that is a substantially planar annularbody that extends radially outward from the tubular member 710 at thesecond end 714 of the device 700.

In use, the device 700 is inserted into the patient's body until theflange 720 or other stop surface engages an external part 32 of thepatient's body, thus restraining the device 700 against being inserteddeeper into the patient's body. The external part 32 of the patient'sbody can be, for example, a portion of the patient's body that islocated outside of and adjacent to an anal sphincter or vaginal openingof the patient. In a first position (FIG. 7A), the tip 22 of theapplicator member 20 is disposed within the hollow interior of thetubular member 710 of the device 700, at a location that is adjacent tothe second end 714 of the tubular member 710. As the tip 22 is movedthrough the tubular member 710 toward the first end 712, the tip 22contacts the topical pharmaceutical composition 702 and displaces itwithin the tubular member 710 such that the topical pharmaceuticalcomposition 702 is pushed through the tubular member 710 in response tomovement of the tip 22 of the applicator member 20. When the tip 22reaches the first end 712 of the tubular member 710, the topicalpharmaceutical composition 702 exits the first end 712 of the device 700along with the tip 22 of the applicator member 20, and the topicalpharmaceutical composition 702 is delivered to the treatment site 10 bythe tip 22 (FIG. 7B). Optionally, the tip 22 of the applicator member 20can then be engaged with the treatment site 10 for applying pressure tothe treatment site 10.

It should be understood that the features of the devices described withrespect to FIGS. 1-7B can be combined in any desired fashion. As anexample, the stop surface described with respect to the device 700 canbe incorporated in the device 500. Other combinations of features arepossible.

It should be understood that the devices shown in FIGS. 1-7B can bereusable devices or can be disposable devices.

The devices described with respect to FIGS. 1-7B can be utilized in amethod for treating pelvic pain syndromes. The method includes placing adesired amount of the topical pharmaceutical composition within thedevice, inserting the device partially into a rectal or vaginal cavityof a patient, moving a part of an applicator member, such as a tip ofthe applicator member, into a hollow interior of the device, and movingthe applicator member through the device such that the topicalpreparation is forced out of the device and is directed toward thetreatment site. The method can further include applying pressure to thetreatment site using at least one of the device or the applicatormember. By this method, the applicator member can press thepharmaceutical composition against tender trigger points and areas ofmyofascial restriction that are higher inside the pelvic floor thanwould be accessible by application with a gloved finger, and the tip ofthe pressure applicator member can be guided by the patient's subjectivesenses, based on the sensations experienced by the patient.

Further devices include internal trigger point wands (see, e.g. U.S.Pat. Nos. 8,337,435 and 8,224,464, each of which is incorporated hereinby reference in its entirety for all purposes).

Drug Applicator Sleeve

In accordance with another aspect of the disclosure herein, delivery ofa topical pharmaceutical composition to a treatment site within therectal cavity or the vaginal cavity of a human patient can be aided bythe use of a drug applicator sleeve, which encases a medical probe, forexample but not limitation an internal trigger point wand. In oneembodiment, the drug applicator sleeve is an elongated tube with oneopen and one closed end. The probe or wand is inserted within the sleeveso that the probe is covered by the sleeve while in use inside the body.In this way, the sleeve is similar to an ultrasound probe cover orcondom. Disposed along the length of the sleeve is a conduit capable ofcarrying and applying a topical pharmaceutical composition, as definedsupra.

FIG. 8A shows an example of a representative drug applicator sleeve ofthe invention. Sleeve 500 has open end 501 and closed end 502.Integrally attached to sleeve 500 is conduit 600, having proximate openend 601 and distal open end 602. Proximate open end 601 has optionallyattached thereto receiver 603, which is a receiving mechanism for asyringe, bulb or other reservoir commonly used to dispense medicaments,for example and not limitation a Luer-Lock for a syringe. Although FIG.8A shows the conduit disposed on the outside of the sleeve, theinvention also includes embodiments wherein the conduit is disposedinside the sleeve, and wherein the conduit forms part of the sleeve, asshown in cross sections 8 b, 8 c and 8 d.

Conduit open end 602 can be adapted to open in a single location ormultiple locations. In some embodiments, Conduit open end 602 is adaptedto deliver a topical pharmaceutical composition to a specific place, forexample by having a reduction in size at the opening so as to restrictthe flow out of the conduit, and/or by having a different material atthe end of open end 602.

Preferably, the drug applicator sleeve is configured to deliver topicalpharmaceutical compositions, like those described supra, to pointswithin the rectal or vaginal cavity. In some embodiments, the sleeve isused with a medical probe, for example but not limitation an internaltrigger point wand (for example those described in U.S. Pat. Nos.8,337,435 and 8,224,464). During use, a medical probe or trigger pointwand is inserted into sleeve 500, and the probe or wand is used in itsusual fashion to apply pressure to internal trigger points of, forexample, the vaginal or rectal cavities. When application of a topicalpharmaceutical composition is desired, a bulb, syringe or other suitablereservoir containing the composition is attached to receiver 603, andthe bulb, syringe or other reservoir is employed to expel thecomposition through conduit 600 and out of conduit end 602 in preciselythe desired location.

In some embodiments, the drug applicator sleeve is disposable. In someother embodiments, the drug applicator sleeve is reusable.

The drug applicator sleeve is preferably made of a flexible,biocompatible material which is preferably resistant to tears orpunctures. The sleeve may be composed of any suitable elastomericmaterial; examples of suitable materials include but are not limited to:natural rubber latex, acrylonitrile, polyvinyl chloride, polyethylene,polypropylene, etc. Preferably, the sleeve is flexible, for example andnot limitation having comparable flexibility to condoms, elastomericmedical examination gloves, and the like.

The conduit is preferably a flexible channel which is integral to, andresides passively on or in, the sleeve. The conduit can be made from anysuitable elastomeric material, including those suitable for use as thesleeve. In some preferred embodiments, the conduit is made from the sameor similar material as the sleeve. Thus, in some embodiments, theflexibility of both the conduit and the sleeve are comparable. In someembodiments, the conduit is disposed along the interior or exteriorsurface of the sleeve, or within the walls of the sleeve, as shown inFIGS. 8a -8 c.

Typically, the drug applicator sleeve is from about 2 to about 10 incheslong, and about one eighth (⅛) inch to about 2 inches in diameter,depending upon the probe or wand desired. The conduit can be from aboutone sixth (⅙) inch to about 1 inch in diameter, depending upon theproperties of the desired pharmaceutical composition, e.g., flowproperties, viscosity, etc. In some embodiments, the drug applicatorsleeve is a smooth tube. In other embodiments, the drug applicatorsleeve is adapted to conform to the surfaces of a probe or trigger pointwand.

In some embodiments, the conduit is pre-filled with a pharmaceuticalcomposition, such as for example a topical pharmaceutical composition ofthe invention as described herein. In some such embodiments, thepre-filled conduit enables users to administer pre-dosed amounts ofcompositions.

In some such embodiments, when pressure is applied to the conduit fromthe bulb, syringe or other reservoir, the composition is forced throughthe conduit and exits at end 602. In some embodiments, the conduit isunfilled, and is filled during use by expulsion of a topicalpharmaceutical composition from, for example, a syringe, and into theconduit as described above.

FIG. 9 shows an internal trigger point wand 400 inserted into a drugapplicator sleeve of the invention 500. Conduit 600 can be prefilledwith a therapeutic composition or unfilled. Receiver 603 can be attachedto a syringe, bulb or other reservoir as described above, and thecontents of the reservoir and/or conduit deposited through open end 602to the place of pressure application. When the patient has the wandinside the body and locates a trigger point, he or she would inject asmall amount of the composition, for example a topical nifedipinecomposition as described herein, at the end of the wand. Then throughthe pressure of the trigger point release, the composition would be‘pressed’ onto and “into” the tissue, abetting its local absorption. Thepatient would hold the pressure for 30-90 seconds as is customary fortrigger point release and then move on to the next trigger point ortender area and repeat the procedure there.

The compounds and compositions disclosed herein may also be used incombination with one or more other active ingredients. In certainembodiments, the compounds may be administered in combination, orsequentially, with another therapeutic agent. Such other therapeuticagents include those known for treatment, prevention, or amelioration ofone or more symptoms associated with pain conditions.

Provided herein is method (Method 1) for treating prostatitis categoryIIIA and/or IIIB in a male patient comprising administering to the malepatient in need thereof a therapeutically effective amount of an activeagent as described herein (i.e., a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, hydrates, solvates andprodrugs thereof). In some embodiments, the prostatitis category IIIAand/or IIIB is associated with pelvic floor muscle trigger points and/orareas of myofascial restriction.

Further provided herein is method (Method 2) for treating a conditionselected from chronic pelvic pain, chronic pelvic pain without fissuresor fistulas, chronically trigger pointed muscles, chronically triggerpointed pelvic floor muscles, chronic pelvic pain syndrome, pelvic floormyalgia, pelvic floor dysfunction, interstitial cystitis, levator anisyndrome, coccygodynia, prostatodynia, piriformis syndrome, vaginismus,anismus, anal sphincter pain, bowel movement pain, post bowel movementpain, ejaculatory pain or post ejaculatory pain in a patient comprisingadministering to the patient in need thereof a therapeutically effectiveamount of an active agent as described herein. In some embodiments, thecondition is associated with pelvic floor muscle trigger points and/orareas of myofascial restriction. In some embodiments, the chronic pelvicpain exists without fissures or fistulas or evidence of other pathologyin external or internal anal sphincters; and the chronic pelvic painsyndrome exists with pain referring trigger points. In some embodiments,the condition is associated with pelvic floor muscle trigger pointsand/or areas of myofascial restriction

Further provided herein is method (Method 3) for treating sitting pain,post bowel movement pain, rectal pain, tailbone pain, urinary frequency,urinary urgency, urinary hesitancy, perineal pain, penile pain, sexualdysfunction and reduced level of ejaculate or reduced penile erection ina patient comprising administering to the patient in need thereof atherapeutically effective amount of an active agent as described herein.In some embodiments, the sitting pain, post bowel movement pain, rectalpain, tailbone pain, urinary frequency, urinary urgency, urinaryhesitancy, perineal pain, penile pain, sexual dysfunction and reducedlevel of ejaculate or reduced penile erection exists in the presence ofor is associated with pelvic floor muscle trigger points and/or areas ofmyofascial restriction.

Further provided herein is method (Method 4) for treating myofascialpain in muscle tissue of a patient who has one or more trigger points inthe muscle tissue comprising administering to the one or more triggerpoints of the patient in need thereof a therapeutically effective amountof an active agent as described herein.

Further provided herein is method (Method 5) for reducing thepain/sensitivity of pelvic floor muscle trigger points and specificareas of myofascial restriction detected upon palpation in a patient,comprising applying to the patient in need thereof a therapeuticallyeffective amount of an active agent as described herein. In someembodiments of Method 5, the patient is a female. In some suchembodiments, the pelvic pain is not associated with hypertonus.

Further provided herein is method (Method 6) for treating pelvic pain orin a female patient comprising administering to the patient in needthereof a therapeutically effective amount of an active agent asdescribed herein. In some embodiments of Method 6, the pelvis of thefemale or male patient is not hypertonic. In some embodiments of Method6, the calcium channel blocker or 1-arginine is not administered to thevagina of the patient.

Further provided herein is method (Method 7) for reducing or resolvingtrigger point pain, sensitivity or activity in muscle of a patient inneed thereof comprising contacting the muscle with a therapeuticallyeffective amount of an active agent as described herein. In someembodiments, the therapeutically effective amount of the active agent isadministered to, near to or adjacent to one or more external or internaltrigger points of the muscle. In some embodiments, the muscle is locatedin the anal sphincter, beyond the internal anal sphincter in the pelvicfloor, in the superior portions of the levator ani muscles, in thecoccygeus muscles, in the obturator internus muscles, in the internalportions of the piriformis; in an external muscle; in the rectusabdominus, in a gluteal muscle, in an adductor muscle, or the quadratuslumborum. In some embodiments, the contacting comprises administeringthe active agent to the pelvic floor muscle of the patient; or to one ormore specific trigger points in the pelvic floor muscle of the patient;or near to, or adjacent to, one or more specific trigger points in thepelvic floor muscle of the patient.

In further embodiments, the present inventions provides methods (Method8) for the reduction and/or resolution of trigger point pain,sensitivity or activity in a muscle of a patient in need thereof,comprising administering a therapeutically effective amount of a calciumchannel blocker, or L-arginine, or a combination of a calcium channelblocker and L-arginine, or pharmaceutically acceptable salts, hydrates,solvates and prodrugs thereof to the muscle of the patient. In someembodiments, the one or more trigger points are external trigger points.In some embodiments, the active agent is administered by injection, forexample directly into or near to, or adjacent to the trigger point bythe patient or another, for example a doctor or physical therapist. Insome embodiments, the active agent is administered manually. In someembodiments, the active agent is administered directly to, near to, oradjacent to one or more trigger points of the muscle. In someembodiments, the method comprises self-treatment. In other embodiments,the method is comprises treatment by another. In other embodiments, themethod comprises administration of the active agent by the patient aspart of a self-treatment program, for example by using an internaltrigger point wand.

In further embodiments, the present inventions provides methods (Method9) for relieving muscle soreness or pain in a patient in need thereof,comprising applying to the muscle a topical composition comprising acalcium channel blocker, or a pharmaceutically acceptable salt, hydrate,solvate or prodrug thereof. In some such embodiments, a topicalcomposition is applied to the muscle. In some embodiments, the topicalcomposition is a balm, which can comprise one or more analgesics,fragrances and excipients, for example and not limitation menthol,menthone, camphor, pulegol, isopulegol, cineole, mint oil, peppermintoil, spearmint oil, eucalyptus oil, 3-(1-menthoxy)propane-1,2-diol,N-alkyl-p-menthane-3-carboxamide,2-methyl-3-(1-menthoxy)propane-1,2-diol, p-menthane-3,8-diol,2-(1-menthoxy)ethan-1-ol, 3-(1-menthoxy)propan-1-ol,4-(1-menthoxy)butan-1-ol, menthyl 3-hydroxybutanoate, menthyl lactate,menthone glycerin ketal, N-methyl-2,2-isopropylmethyl-3-methylbutaneamide, menthyl glyoxylate cajuput oil, clove oil, dementholized mint oiland paraffin petrolatum.

In further embodiments, the present inventions provides methods (Method10) for relieving one or more symptoms of carpal tunnel syndrome in apatient in need thereof, comprising administering to a patient in needthereof a pharmaceutical composition comprising a calcium channelblocker, or a pharmaceutically acceptable salt, hydrate, solvate orprodrug thereof. In some such embodiments, a topical composition isapplied to the muscle. In other such embodiments, an oral pharmaceuticalcomposition is administered.

The present invention further provides a method (Method 11) of treatinga condition selected from chronic pelvic pain, chronic pelvic painwithout fissures or fistulas, chronically trigger pointed muscles,chronically trigger pointed pelvic floor muscles, chronic pelvic painsyndrome, pelvic floor myalgia, pelvic floor dysfunction, interstitialcystitis, levator ani syndrome, coccygodynia, prostatodynia, piriformissyndrome, vaginismus, anismus, anal sphincter pain, bowel movement pain,post bowel movement pain, ejaculatory pain or post ejaculatory pain;chronic pelvic pain without evidence of other pathology in external orinternal anal sphincters; pelvic pain with pain referring triggerpoints; pelvic pain with associated with pelvic floor muscle triggerpoints and/or areas of myofascial restriction; sitting pain, post bowelmovement pain, rectal pain, tailbone pain, urinary frequency, urinaryurgency, urinary hesitancy, perineal pain, penile pain, vaginismus,anismus, sexual dysfunction and reduced level of ejaculate or reducedpenile erection, urinary sphincter spasms, urethral sphincter spasms,post urinary pain, rectal sphincter spasms, proctalgia fugax andmyofascial pain in muscle tissue of a patient who has one or moretrigger points in the muscle tissue; the method comprising treating apatient in need thereof with a dilator, such as an anal, vaginal orurethral dilator (including pediatric dilators thereof).

In some embodiments of Method 11, dilators for use in accordance withthe methods of the invention are preferably are preferably sized from ¼inch in diameter to 1½″ inches in diameter, for example in sizeincrements of 1/16 or ⅛ of an inch. In some preferred embodiments, themethods of the invention comprise the use of the dilators daily, or morethan once daily, for example twice daily, three times daily, or more,for a period of time at each instance, for example of from about 10minute to about 40 minutes, or about 20 minutes to about 30 minutes. Insome embodiments, the methods of the invention are employed for a fixedperiod of time, for example on a single day, for several days, a week, 1month, or longer. In some embodiments, treatment with the methods of theinvention is continued until symptoms are resolved. In some embodiments,treatment further comprises the progressive transitioning from smallersized dilators to larger sized dilators.

The invention further provides a kit containing a plurality of dilatorshaving sizes from about ¼ inch in diameter to about 1½″ inches indiameter, in size increments of for example 1/16 or ⅛ of an inch. Inpreferred embodiments, the dilator kits include an application guide forinstructing the patient or health care professional in the proper use ofthe dilator in accordance with the methods of the invention.

In some embodiments, Method 11 further comprises the administration of acalcium channel blocker, or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof, as described herein. Thecalcium channel blocker can be administered orally (e.g., as an oralcomposition), for example, in the form of a pill, tablet or capsule; ortopically (e.g., as a topical composition), such as an ointment, gel orpaste. In some embodiments, the calcium channel blocker, orpharmaceutical composition thereof, is administered prior to use of thedilator, for example from 5 minutes to 60 minutes prior to dilator use,from 10 minutes to 60 minutes prior to dilator use; from 20 minutes to60 minutes prior to dilator use; or from 30 to 60 minutes prior todilator use. In some embodiments, a local anesthetic agent may also beadministered concomitantly or sequentially with dilator use. In someembodiments, the local anesthetic is a component of the pharmaceuticalcomposition containing the calcium channel blocker. In some preferredembodiments, the calcium channel blocker used with Method 11 isnifedipine.

In some embodiments of the methods 1-11 described herein, the activeagent includes a corticosteroid, for example cortisone orhydrocortisone.

In some embodiments of each of the methods described herein, the methodsare performed in the presence of muscle hypertonicity. In someembodiments of each of the methods described herein, the methods areperformed in the absence of muscle hypertonicity.

In some embodiments of each of the methods described herein, the methodsinclude treating the recited pain condition wherein the condition isassociated with specific areas of myofascial restriction, for examplethose detected upon palpation in a patient.

In some embodiments of each of the methods described herein, theadministration of the active agent is performed manually, or using anapplicator such as a syringe or an internal trigger point wand asdescribed herein, or via injection. In some embodiments theadministration of the active agent is performed via injection into, nearto or adjacent to the muscle. In some embodiments, the active agent isinjected directly into, near to or adjacent to one or more triggerpoints of the muscle. In some embodiments, the trigger points areexternal trigger points, and in other embodiments, the trigger pointsare internal trigger points.

In some embodiments of each of the methods and compositions describedherein, the active agent is present in a pharmaceutical composition thatfurther comprises one or more pharmaceutically acceptable carriers, andoptionally an anesthetic.

Further provided herein are any of the foregoing methods wherein thecalcium channel blocker is a dihyropyridine, a phenylalkylamine, abenzothiapene, zicotonide or a nonselective calcium channel blocker.

Further provided herein are any of the foregoing methods wherein thedihydropyridine channel blocker is amlopidine, aranidipine,azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine,isradipine, efonidipine, felodipine, lacidipone, lercanidipine,manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,nisoldipine, nitrendipine or pranidipine

Further provided herein are any of the foregoing methods wherein thephenylalkylamine calcium channel blocker is varapamil, gallopamil orfendiline.

Further provided herein are any of the foregoing methods wherein thebenzothiazepine calcium channel blocker is diltiazem.

Further provided herein are any of the foregoing methods wherein thenon-selective calcium channel blocker is mibefradil, bepridil,flunarizine, fluspirilene or fendiline.

Further provided herein are any of the foregoing methods wherein thecalcium channel blocker is diltiazem or nifedipine.

Further provided herein are any of the foregoing methods wherein thecalcium channel blocker is nifedipine.

Further provided herein are any of the foregoing methods comprisingadministering to the patient in need thereof a pharmaceuticalcomposition comprising the therapeutically effective amount of thecalcium channel blocker, or L-arginine, or combination of a calciumchannel blocker and L-arginine, or pharmaceutically acceptable salts,hydrates, solvates and prodrugs thereof. In some embodiments, thepharmaceutical composition further comprises a therapeutically effectiveamount of a local anesthetic. In some embodiments, the local anestheticis lidocaine.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition further comprises a controlled release agent.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition comprises a poloxamer. In some suchembodiments, the poloxamer is poloxamer 407®.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition comprises diltiazem or nifedipine.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition comprises nifedipine and a controlled releaseagent.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition comprises diltiazem and a controlled releaseagent.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition is topical.

Further provided herein are any of the foregoing methods wherein thetopical pharmaceutical composition is applied to a treatment site.

Further provided herein are any of the foregoing methods wherein thetreatment site is the inside of an anal opening or the pelvic floormuscles of the patient.

Further provided herein are any of the foregoing methods wherein thetreatment site is the vaginal opening of a female patient.

Further provided herein are any of the foregoing methods wherein thetopical pharmaceutical composition is applied to the anal sphincter orvaginal opening of the patient by inserting a pressure applicator devicein a rectal cavity or a vaginal cavity of the human patient through theanal sphincter or vaginal opening; and applying pressure at an internaltrigger point or area of myofascial restriction within the rectal cavityor the vaginal cavity with the pressure applicator device to apply thetopical pharmaceutical composition.

Further provided herein are any of the foregoing methods wherein thetopical pharmaceutical composition is applied manually, as a suppositoryor using an applicator. In some embodiments, the topical pharmaceuticalcomposition is applied using a disposable or reusable rectal syringe, ora pressure applicator device.

Further provided herein are any of the methods described herein furthercomprising the step of identifying a patient in need of the treatment.

Further provided herein are any of the foregoing methods wherein thepharmaceutical composition comprises the calcium channel blocker in anamount of from 0.5% to 5%; or from 0.5% to 4%; or from 0.5% to 3%; orfrom 0.5% to 2%; or from 0.5% to 1.5%; or 1%, 2%, 3%, 4% or 5% byweight. In some such embodiments, the calcium channel blocker isdiltiazem or nifedipine.

The present invention further provides topical pharmaceuticalcompositions comprising a calcium channel blocker, or L-arginine, or acombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts, hydrates, solvates and prodrugsthereof, in an amount therapeutically effective to treat one or more ofchronic pelvic pain, trigger pointed pelvic floor muscles, chronicpelvic pain syndrome, pelvic floor myalgia, pelvic floor dysfunction,interstitial cystitis, levator ani syndrome, coccygodynia,prostatodynia, piriformis syndrome, anal sphincter pain, bowel movementpain, post bowel movement pain, ejaculatory pain, post ejaculatory pain,sitting pain, post bowel movement pain, rectal pain, tailbone pain,urinary frequency, urinary urgency, urinary hesitancy, perineal pain,penile pain, sexual dysfunction, reduced level of ejaculate or reducedpenile erection, myofascial pain in muscle tissue of a patient who hasone or more trigger points in the muscle tissue, conditionscharacterized by muscle spasm or soreness such as, for example, urinarysphincter spasms, urethral sphincter spasms, post urinary pain, rectalsphincter spasms and proctalgia fugax, and the pain/sensitivity ofpelvic floor muscle trigger points and specific areas of myofascialrestriction detected upon palpation in a patient. In some embodiments,the calcium channel blocker is diltiazem or nifedipine.

In some embodiments of each of the topical and injectable pharmaceuticalcompositions described herein, the composition can include atherapeutically effective amount of a corticosteroid, for example andnot limitation cortisone and hydrocortisone (cortisol). In someembodiments, the corticosteroid is present in the pharmaceuticalcomposition in an amount of from about from 0.01% to 5% by weight; 0.05%to 4% by weight; 0.1% to 4% by weight; 0.1% to 3% by weight; from 0.1%to 2% by weight; or from 0.5% to 1.5% by weight, or about 0.1%, 0.5%,1%, 1.5%, 2%, 2.5%, 3%, 4% or 5% by weight.

In some embodiments, the topical pharmaceutical composition comprises apoloxamer, for example poloxamer 407®. While not wishing to be bound byany particular theory, it is believed that poloxamers, and in particularpoloxamer 407® are advantageous in that the combination of the poloxamerplus calcium channel blocker, for example and not limitation nifedipineor diltiazem, and/or L-arginine, forms a unique composition that hasbioadhesive and healing properties. It also is believed that thecomposition has the beneficial property of increasing in viscosity orsolidity as its temperature increases. These properties may bebeneficial in promoting the local administration of the activeingredient(s), and resisting systemic absorption. Indeed, in themethodology discussed in the Wise publications mentioned above, patientsare taught the anatomy of pelvic floor, and the application of pressurein specific areas in the pelvic floor to relieve trigger point activity,either manually or using an applicator such as a syringe or an internaltrigger point wand as described in, e.g. U.S. Pat. Nos. 8,337,435 and8,224,464, each of which is incorporated herein by reference in itsentirety for all purposes. In some embodiments of the present invention,the patient uses the wand to deliver a bioadhesive product of theinvention; e.g., a composition comprising poloxamer 407® and a calciumchannel blocker, L-arginine, or both, to the specific area. It isbelieved that the bioadhesive properties of the composition retardsmigration of the composition, thus promoting the retention of activeingredients in the specific place it is most effective, and thus alsominimizing systemic absorption.

In some embodiments, the topical pharmaceutical composition comprises alocal anesthetic, for example lidocaine.

In some embodiments, the topical pharmaceutical composition comprisesdiltiazem or nifedipine in an amount of from 0.5% to 5% by weight; 0.2%to 5% by weight; 0.5% to 4% by weight; 0.5% to 3% by weight; 0.5% to 2%by weight; or from 0.5% to 1.5% by weight; or about 0.5%, 1%, 1.5%, 2%,2.5%, 3%, 4% or 5% by weight.

In some embodiments, the topical pharmaceutical composition comprisesL-arginine in an amount of from 0.5% to 5% by weight; 0.4% to 4% byweight; 0.5% to 4% by weight; 0.5% to 3% by weight; 0.5% to 2% byweight; or from 0.5% to 1.5% by weight; or about 0.5%, 1%, 1.5%, 2%,2.5%, 3%, 4% or 5% by weight.

In some preferred embodiments, for example those comprising nifedipineas a calcium channel blocker, preferred dosages include a) for a topicalformulation containing 0.5% nifedipine: 3 mg/dose, 6 mg for two doses,and 9 mg for 3 doses; b) for a topical formulation containing 1%nifedipine: 6 mg/dose, 12 mg for two doses, and 18 mg for 3 doses; c)for a topical formulation containing 2% nifedipine: 12 mg/dose, 24 mgfor two doses, and 36 mg for 3 doses; and d) for a topical formulationcontaining 3% nifedipine: 18 mg/dose, 36 mg for two doses, and 54 mg for3 doses.

In some embodiments, the invention provides pharmaceutical compositionsfor oral administration in accordance with the methods described herein,comprising nifedipine in an amount of from 1, 2, 3, 4, 5, 6, 7, 8, 9,11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 100, 110 or 120 mg; or 11, 12, 13, 14, 15, 16, 17, 18,19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89 mg; or 21, 22,23, 24, 25, 26, 27, 28, 29, 31, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50,52, 54, 56, 58, 59, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 8, 86,88, or 89 mg. In some embodiments, the pharmaceutical composition is anextended release composition. In some embodiment, the pharmaceuticalcomposition is an immediate release composition.

In some embodiments the extended release composition contain nifedipinein an amount of 3 mg, 5 mg, 6 mg, 9 mg, 12 mg, 15 mg, 18 mg, 21 mg, 24mg, 25 mg, 27 mg or 29 mg of nifedipine; or in an amount of 32 mg, 35mg, 38 mg, 40 mg, 41 mg, 45 mg, 48 mg, 50 mg, 55 mg, 58 mg, 62 mg, 65mg, 70 mg, 75 mg, 80 mg, 85 mg or 89 mg of nifedipine.

In some embodiments, the invention provides an extended releasepharmaceutical composition for oral administration in accordance withthe methods described herein, comprising diltiazem in an amount of from20 mg to 170 mg, for example for example 2, 5, 10, 20, 30, 40, 50, 60,70, 80, 90, 100, 110, 120, 130, 140, 150, 160 or 170 mg of diltiazem.

In some further embodiments, the invention provides an immediate releasepharmaceutical composition for oral administration comprising nifedipinein an amount of from 1-27 mg, for example 1 mg, 2 mg, 3 mg, 6 mg, 9 mg,12 mg, 15 mg, 18 mg, 21 mg, 24 mg or 27 mg of diltiazem.

In some embodiments, the invention provides an extended release,enterically coated dosage form comprising an active ingredient that is acalcium channel blocker, for example nifedipine or diltiazem, whereinthe dosage form additionally comprises one or more mucoadhesivepolymers, and, optionally, one or more delayed release polymers. Theinvention further provides a method for simultaneously delivering asystemic and local acting dose of a calcium channel blocker, comprisingadministering such a dosage form.

In some embodiments, the invention provides the foregoing methodsdescribed herein, the methods comprising the administration of apharmaceutical composition for oral administration as described herein.

Further provided in accordance with the present invention is a methodfor treating chronic pelvic pain, chronically trigger pointed pelvicfloor muscles, chronic pelvic pain syndrome, pelvic floor myalgia,pelvic floor dysfunction, interstitial cystitis, levator ani syndrome,coccygodynia, prostatodynia, piriformis syndrome, anal sphincter pain,bowel movement pain, post bowel movement pain, ejaculatory pain, postejaculatory pain, sitting pain, post bowel movement pain, rectal pain,tailbone pain, urinary frequency, urinary urgency, urinary hesitancy,perineal pain, penile pain, vaginismus, anismus, sexual dysfunction,reduced level of ejaculate or reduced penile erection, myofascial painin muscle tissue of a patient who has one or more trigger points in themuscle tissue, or the pain/sensitivity of pelvic floor muscle triggerpoints detected upon palpation in a patient; the method comprising:

-   -   a) palpating a patient to detect said trigger points; and    -   b) administering to the identified trigger points and/or        specific areas of myofascial restriction of the patient a        therapeutically effective amount of a calcium channel blocker,        or L-arginine, or a combination of a calcium channel blocker and        L-arginine, or pharmaceutically acceptable salts, hydrates,        solvates and prodrugs thereof, as described in the foregoing        methods and compositions herein. The administration in some        embodiments can be performed by the patient, a therapist, or        another.

The present invention also provides compositions and methods fortreatment of anal fissures, and alleviation of symptoms of analfissures, which in one embodiment comprises perianal or intrarectaladministration of a topical composition comprising the activeingredients according to the present invention, for example nifedipineor diltiazem, and in a further embodiment comprises oral administrationof the active ingredients according to the present invention, forexample nifedipine or diltiazem, each to a patient in need thereof. Insome embodiments, the methods comprise administration of a topicalpharmaceutical composition comprising nifedipine in an amount of from0.3-2%; or an oral dose of from 11 mg to 90 mg of nifedipine, asdescribed above; or a topical pharmaceutical composition comprisingdiltiazem in an amount of from 1-3%; or an oral dose of from 120 mg to360 mg of diltiazem; each optionally containing one or more excipients,for example and not limitation a poloxamer, for example poloxamer 407.

The present invention further provides methods for treating a conditioncharacterized by muscle spasm or soreness, comprising administering to apatient in need thereof a therapeutically effective amount of a calciumchannel blocker, or L-arginine, or a combination of a calcium channelblocker and L-arginine, or pharmaceutically acceptable salts thereof. Insome embodiments, the condition is selected from urinary sphincterspasms, urethral sphincter spasms, post urinary pain, rectal sphincterspasms and proctalgia fugax In some such embodiments, the methodscomprise oral or topical administration of the calcium channel blocker,or pharmaceutically acceptable salt thereof, preferably in an extendedrelease oral dosage form. In some embodiments of the foregoing, thecalcium channel blocker is selected from nifedipine and diltiazem.

The present invention further provides an apparatus for applying atopical pharmaceutical composition to a treatment site that is locatedwithin a rectal cavity or a vaginal cavity of a human patient, theapparatus comprising: a tubular member, wherein the topicalpharmaceutical composition is located inside the tubular member prior toapplication of the topical preparation to the treatment site; and anapplicator member that is receivable in the sleeve wherein, theapplicator member is movable within the tubular member from a firstposition to a second position to cause at least a portion of the topicalpreparation to be moved out of the sleeve and thereby applied to thetreatment site.

In some embodiments of the apparatus, wherein the tubular member isadapted to extend into an opening of the rectal cavity or the vaginalcavity of the human patient. In some further embodiments of theapparatus, the tubular member extends from a first end to a second end,wherein the first end is disposed within the rectal cavity or thevaginal cavity of the human patient during application of the topicalpharmaceutical composition to the treatment site and the second end isdisposed outside of the rectal cavity or the vaginal cavity of the humanpatient during application of the topical pharmaceutical composition tothe treatment site.

In some further embodiments of the apparatus, the tubular member extendsfrom a first end to a second end, wherein the first end is disposedwithin the rectal cavity or the vaginal cavity of the human patientduring application of the topical pharmaceutical composition to thetreatment site and the second end is disposed outside of the rectalcavity or the vaginal cavity of the human patient during application ofthe topical pharmaceutical composition to the treatment site. In somesuch embodiments, the first end has a semi-spherical configurationdefined by a plurality of segments that are movable in response tomovement of the applicator member from the first position to the secondposition.

In some embodiments, the apparatus further comprises a stop surface thatextends outward from the tubular member for restraining furtherinsertion of the tubular member with respect to the rectal cavity or thevaginal cavity of the human patient.

In some embodiments, the pharmaceutical compositions described hereinare applied manually (for example by using a gloved finger), or using anapplicator as described herein, for example and not limitation thepressure applicator device described above, or using commerciallyavailable disposable or re-useable rectal syringes. Accordingly, thepresent invention further provides kits comprising one or moredisposable rectal syringes and a pharmaceutical composition according tothe invention. The invention further provides kits comprising one ormore re-useable or disposable rectal syringes and a pharmaceuticalcomposition according the invention. The invention further provides kitscomprising one or more applicators as described herein and apharmaceutical composition according the invention.

In some embodiments of each of the foregoing kits, the syringes orapplicators can be pre-filled with the pharmaceutical composition.

In some embodiments, the pharmaceutical compositions described hereinare applied using an internal trigger point wand. Such wands aredescribed in, e.g. U.S. Pat. Nos. 8,337,435 and 8,224,464, each of whichis incorporated herein by reference in its entirety for all purposes.

In some embodiments, the invention provides drug applicator sleevescomprising: a tubular member having an open end and a closed end; and anintegral conduit disposed thereon or therein; wherein: the tubularmember has a length of from about 2 to about 10 inches long, and adiameter of from about ⅛ inch to about 2 inches; the integral conduithas a diameter of from ⅙ inch to about 1 inch, and also optionallycomprises a receiver for interfacing with a syringe, bulb or otherreservoir. In some embodiments, the integral conduit is disposed on orin the tubular member substantially along its length.

In some embodiments, the drug applicator sleeve is a smooth tube, and inother embodiments, drug applicator sleeve is adapted to conform to thesurfaces of a probe or trigger point wand. In some embodiments, theintegral conduit comprises a receiver for interfacing with a syringe,bulb or other reservoir.

In some of each of the foregoing embodiments, the conduit is pre-filledwith a topical pharmaceutical composition. In some such embodiments, thetopical pharmaceutical composition is a composition of the invention asdescribed herein.

Also provided in accordance with the invention are assemblies comprisinga medical probe or trigger point wand and a drug applicator sleeve asdescribed herein.

Also provided in accordance with the present invention are:

-   -   a) the use of diltiazem, nifedipine or L-arginine to treat        prostatitis category IIIA and/or IIIB in a male patient;    -   b) the use of diltiazem, nifedipine or L-arginine to treat        chronic pelvic pain, chronic pelvic pain syndrome, pelvic floor        myalgia, pelvic floor dysfunction, interstitial cystitis,        levator ani syndrome, coccygodynia, prostatodynia, piriformis        syndrome, anal sphincter pain, bowel movement pain, post bowel        movement pain, ejaculatory pain or post ejaculatory pain;    -   c) the use of diltiazem, nifedipine or L-arginine to treat        sitting pain, post bowel movement pain, rectal pain, tailbone        pain, urinary frequency, urinary urgency, urinary hesitancy,        perineal pain, penile pain, sexual dysfunction and reduced level        of ejaculate or reduced penile erection;    -   d) the use of diltiazem, nifedipine or L-arginine to treat        myofascial pain in muscle tissue of a patient who has one or        more trigger points in the muscle tissue;    -   e) the use of diltiazem, nifedipine or L-arginine to reduce the        pain/sensitivity of pelvic floor muscle trigger points detected        upon palpation in a patient used topically and applied to the        patient manually, such as with a gloved finger; and    -   f) the use of diltiazem, nifedipine or L-arginine to treat        pelvic pain in a female patient;    -   g) the use of diltiazem, nifedipine or L-arginine to treat anal        sphincter pain, bowel movement pain, post bowel movement pain,        ejaculatory pain, ejaculatory discomfort, post ejaculatory pain,        sitting pain, rectal pain, tailbone pain, urinary frequency,        urinary urgency, urinary hesitancy, perineal pain, penile pain,        sexual dysfunction, reduced level of ejaculate or reduced penile        erection, nonbacterial prostatitis, slow urinary flow, reduced        urinary flow, post ejaculatory discomfort, urinary or urethral        sphincter spasms and post urinary pain, rectal sphincter spasms,        proctalgia fugax, chronic pelvic pain, pelvic floor muscles        containing trigger points and areas of myofascial restriction,        chronic pelvic pain syndrome, pelvic floor myalgia, pelvic floor        dysfunction, interstitial cystitis, levator ani syndrome,        coccygodynia, prostatodynia, prostadynia, piriformis syndrome,        anal sphincter pain, bowel movement pain, ejaculatory pain,        ejaculatory discomfort, post bowel movement pain, anal fissures        or tear in the anorectal/anal sphincter area, myofascial pain in        muscle tissue of a patient who has one or more trigger points in        the muscle tissue, and the pain/sensitivity of pelvic floor        muscle trigger points and specific areas of myofascial        restriction detected upon palpation in a patient.

The invention provides, in one embodiment, a method (Method 1) fortreating prostatitis category IIIA and/or IIIB in a male patientcomprising administering to the male patient in need thereof atherapeutically effective amount of a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts, for example:

-   1.1. Method 1, wherein the calcium channel blocker is nifedipine or    diltiazem;-   1.2. Method 1 or 1.1, wherein the prostatitis category IIIA and/or    IIIB is associated with pelvic floor muscle trigger points.-   1.3. Any Method 1-1.2, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   1.4. Method 1.3, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 2) fortreating a condition selected from chronic pelvic pain, chronic pelvicpain without fissures or fistulas, chronically trigger pointed pelvicfloor muscles, chronic pelvic pain syndrome, pelvic floor myalgia,pelvic floor dysfunction, interstitial cystitis, overactive bladder,levator ani syndrome, coccygodynia, prostatodynia, piriformis syndrome,anal sphincter pain, bowel movement pain, post bowel movement pain,vaginismus, anismus, ejaculatory pain or post ejaculatory pain in apatient comprising administering to the patient in need thereof atherapeutically effective amount of a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts thereof, for example:

-   2.1. Method 2, wherein the calcium channel blocker is nifedipine or    diltiazem;-   2.2. Method 2 or 2.1, wherein the chronic pelvic pain exists with or    without fissures or fistulas or evidence of hypertonus or other    pathology in external or internal anal sphincters; and the chronic    pelvic pain syndrome exists with pain containing or referring    trigger points.-   2.3. Method 2.2, wherein the condition is associated with pelvic    floor muscle trigger points.-   2.4. Any Method 2-2.2, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   2.5. Method 2.4, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 3) fortreating sitting pain, post bowel movement pain, rectal pain, tailbonepain, urinary frequency, urinary urgency, urinary hesitancy, overactivebladder, perineal pain, penile pain, sexual dysfunction and reducedlevel of ejaculate or reduced penile erection in a patient comprisingadministering to the patient in need thereof a therapeutically effectiveamount of a calcium channel blocker, or L-arginine, or a combination ofa calcium channel blocker and L-arginine, or pharmaceutically acceptablesalts thereof, for example:

-   3.1. Method 3, wherein the calcium channel blocker is nifedipine or    diltiazem;-   3.2. Method 3 or 3.1, wherein the sitting pain, post bowel movement    pain, rectal pain, tailbone pain, urinary frequency, urinary    urgency, urinary hesitancy, overactive bladder, perineal pain,    penile pain, sexual dysfunction and reduced level of ejaculate or    reduced strength penile erection exists in the presence of pelvic    floor muscle trigger points.-   3.3. Any Method 3-3.2, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   3.4. Method 3.3, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 4) oftreating myofascial pain in muscle tissue of a patient who has one ormore trigger points in the muscle tissue comprising administering to theone or more trigger points of the patient in need thereof atherapeutically effective amount of a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts thereof, for example:

-   4.1. Method 4, wherein the calcium channel blocker is nifedipine or    diltiazem.-   4.2. Method 4 or 4.1, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   4.3. Method 4.2, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 5) ofreducing the pain/sensitivity of pelvic floor muscle trigger pointsdetected upon palpation in a patient, comprising applying to the patientin need thereof a therapeutically effective amount of a calcium channelblocker, or L-arginine, or a combination of a calcium channel blockerand L-arginine, or pharmaceutically acceptable salts thereof, forexample:

-   5.1. Method 5, wherein the calcium channel blocker is nifedipine or    diltiazem.-   5.2. Method 5 or 5.1, wherein the patient is a female.-   5.3. Method 5.2, wherein the pelvic pain is not associated with    hypertonus.-   5.4. Any Method 5-5.3, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   5.5. Method 5.4, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 6) oftreating pelvic pain in a female patient comprising administering to thepatient in need thereof a therapeutically effective amount of a calciumchannel blocker, or L-arginine, or a combination of a calcium channelblocker and L-arginine, or pharmaceutically acceptable salts thereof,for example:

-   6.1. Method 6, wherein the calcium channel blocker is nifedipine or    diltiazem.-   6.2. Method 6 or 6.1, wherein the pelvis of the female patient is    not hypertonic.-   6.3. Method 6 or 6.1, wherein the calcium channel blocker or    1-arginine is not administered to the vagina of the patient.-   6.4. Any Method 6-6.3, wherein the administering, applying or    contacting comprises administering the calcium channel blocker, or    L-arginine, or combination of a calcium channel blocker and    L-arginine, or pharmaceutically acceptable salts thereof, to the    pelvic floor muscle of the patient.-   6.5. Method 6.4, wherein the administering, applying or contacting    comprises administering the calcium channel blocker, or L-arginine,    or combination of a calcium channel blocker and L-arginine, or    pharmaceutically acceptable salts thereof, to one or more specific    trigger points in the pelvic floor muscle of the patient.

In further embodiments, the invention provides a method (Method 7) ofreducing or resolving trigger point pain, sensitivity or activity inmuscle of a patient in need thereof comprising contacting the musclewith a therapeutically effective amount of a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts thereof, for example:

-   7.1. Method 7, wherein the calcium channel blocker is nifedipine or    diltiazem.-   7.2. Method 7 or 7.1, wherein the therapeutically effective amount    of a calcium channel blocker, or L-arginine, or a combination of a    calcium channel blocker and L-arginine, or pharmaceutically    acceptable salts thereof is administered on or near one or more    external or internal trigger points of the muscle.-   7.3. Method 7, 7.1 or 7.2, wherein the muscle is located in the anal    sphincter, beyond the internal anal sphincter in the pelvic floor,    in the superior portions of the levator ani muscles, in the    coccygeus muscles, in the obturator internus muscles, in the    internal portions of the piriformis; in an external muscle; in the    rectus abdominus, in a gluteal muscle, in an adductor muscle, or the    quadratus lumborum.-   7.4. Any Method 7-7.3, wherein the contacting comprises injecting    said calcium channel blocker, or L-arginine, or combination of a    calcium channel blocker and L-arginine, or pharmaceutically    acceptable salts thereof, into said muscle.-   7.5. Method 7.4, wherein the contacting comprises injecting said    calcium channel blocker, or

L-arginine, or combination of a calcium channel blocker and L-arginine,or pharmaceutically acceptable salts thereof, directly into, near oradjacent to one or more trigger points of the muscle.

In further embodiments, the invention provides any of the foregoingMethods 1-6.5, wherein the contacting or administering comprisesinjecting the calcium channel blocker, or L-arginine, or combination ofa calcium channel blocker and L-arginine, or pharmaceutically acceptablesalts thereof, into a muscle; for example directly into, near oradjacent to one or more trigger points of the muscle. In some suchembodiments, the calcium channel blocker, or L-arginine, or combinationof a calcium channel blocker and L-arginine, or pharmaceuticallyacceptable salts thereof, is present in a pharmaceutical compositionthat further comprises one or more pharmaceutically acceptable carriers,and optionally an anesthetic.

In further embodiments, the invention provides any of the foregoingMethods 1-7.3, wherein the administering, applying or contacting of thecalcium channel blocker is performed by ingestion of an oral dosage formcomprising the calcium channel blocker, or pharmaceutically acceptablesalt thereof; for example wherein the oral dosage form is a pill, atablet, or a capsule.

In further embodiments, the invention provides any of the foregoingMethods 1-7.3, wherein the administering, applying or contacting of thecalcium channel blocker is performed by application of a topicalcomposition comprising the calcium channel blocker or L-arginine, orpharmaceutically acceptable salt thereof. In some embodiments, theadministration or application of the topical pharmaceutical compositionis intrarectal or perianal. In some embodiments, the topical compositioncomprising the calcium channel blocker, or L-arginine, orpharmaceutically acceptable salt thereof, contains a polyethyleneglycol/polypropylene glycol block copolymer; for example a Poloxamer;for example Poloxamer 407P and/or Poloxamer 188P.

In further embodiments, the invention provides any of the foregoingMethods 1-7.5, wherein the calcium channel blocker is a dihyropyridine,a phenylalkylamine, a benzothiapene, zicotonide or a nonselectivecalcium channel blocker. In some embodiments, the dihydropyridinechannel blocker is amlopidine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, isradipine, efonidipine,felodipine, lacidipone, lercanidipine, manidipine, nicardipine,nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, orpranidipine. In some embodiments, the phenylalkylamine calcium channelblocker is varapamil, gallopamil or fendiline. In some embodiments, thebenzothiazepine calcium channel blocker is diltiazem. In someembodiments, the non-selective calcium channel blocker is mibefradil,bepridil, flunarizine, fluspirilene or fendiline. In some preferredembodiments, the calcium channel blocker is diltiazem or nifedipine,preferably nifedipine.

In further embodiments, the invention provides any of the foregoingMethods 1-7.5, wherein the method (Method 8) comprises administering tothe patient in need thereof a pharmaceutical composition comprising thetherapeutically effective amount of the calcium channel blocker, orL-arginine, or combination of a calcium channel blocker and L-arginine,or pharmaceutically acceptable salts thereof, for example:

-   8.1. Method 8, wherein the pharmaceutical composition further    comprises a therapeutically effective amount of a local anesthetic.-   8.2. Method 8 or 8.1, wherein the pharmaceutical composition further    comprises a controlled release agent.-   8.3. Any Method 8-8.2, wherein the pharmaceutical composition    comprises a poloxamer.-   8.4. Any Method 8-8.3, wherein the poloxamer is poloxamer 407®.-   8.5. Any Method 8-8.4, wherein the pharmaceutical composition    comprises diltiazem or nifedipine.-   8.6. Any Method 8-8.5, wherein the pharmaceutical composition    comprises nifedipine and a controlled release agent.-   8.7. Any Method 8-8.6, wherein the pharmaceutical composition    comprises diltiazem and a controlled release agent.-   8.8. Any Method 8-8.7, wherein the pharmaceutical composition is    topical.-   8.9. Any Method 8-8.8, wherein the topical pharmaceutical    composition is applied to a treatment site.-   8.10. Method 8.9, wherein the treatment site is the inside of an    anal opening or the pelvic floor muscles of the patient.-   8.11. Method 8.9, wherein the treatment site is the vaginal opening    of a female patient.-   8.12. Any Method 8-8.11, wherein the topical pharmaceutical    composition is applied manually, as a suppository, or using an    applicator.-   8.13. Method 8.12, wherein the topical pharmaceutical composition is    applied using a disposable rectal syringe.-   8.14. Method 8.12, wherein the topical pharmaceutical composition is    applied using a reusable rectal syringe.-   8.15. Any Method 8.8-8.14, further comprising administering an oral    dose of a calcium channel blocker, for example nifedipine or    diltiazem.-   8.16. Method 8.15, wherein the oral dose of the calcium channel    blocker is an oral dose of nifedipine.-   8.17. Method 8.15, wherein the oral dose of nifedipine is an    extended release dose.-   8.18. Method 8.15, wherein the oral dose of nifedipine is an    immediate release dose.-   8.19. Method 8.8, wherein the topical pharmaceutical composition is    applied to the anal sphincter or vaginal opening or cavity of the    patient by inserting a pressure applicator device into a rectal    cavity or a vaginal cavity of the human patient through the anal    sphincter or vaginal opening; and applying pressure at an internal    trigger point or area of myofascial restriction within the rectal    cavity or the vaginal cavity with the pressure applicator device to    apply the topical pharmaceutical composition while simultaneously    doing trigger point release.-   8.20. Any Method 8.8-8.15, wherein the pharmaceutical composition    comprises the calcium channel blocker in an amount of from 0.5% to    5% by weight.-   8.21. Any Method 8.8-8.15, wherein the pharmaceutical composition    comprises the calcium channel blocker in an amount of from 0.5% to    4% by weight.-   8.22. Any Method 8.8-8.15, wherein the pharmaceutical composition    comprises the calcium channel blocker in an amount of about 1%; or    about 2%, or about 3%, or about 4%, or about 5% by weight.-   8.23. Any Method 8.16-8.18, wherein the calcium channel blocker is    diltiazem or nifedipine.-   8.24. Any Method 8.16-8.19, wherein the pharmaceutical composition    comprises L-arginine in an amount of from 0.5% to 5% by weight; 0.5%    to 4% by weight; 0.5% to 3% by weight; 0.5% to 2% by weight; or from    0.5% to 1.5% by weight; or about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4% or    5% by weight.

In further embodiments, the invention provides a Method (Method 9) fortreating chronic pelvic pain, pelvic floor myalgia, pelvic floordysfunction, interstitial cystitis, levator ani syndrome, coccygodynia,prostatodynia, piriformis syndrome, anal sphincter pain, bowel movementpain, post bowel movement pain, ejaculatory pain, post ejaculatory pain,sitting pain, post bowel movement pain, rectal pain, tailbone pain,urinary frequency, urinary urgency, urinary hesitancy, overactivebladder, perineal pain, penile pain, vaginismus, anismus, sexualdysfunction, reduced level of ejaculate or reduced penile erection,myofascial pain in muscle tissue of a patient who has one or moretrigger points in the muscle tissue, or the pain/sensitivity of pelvicfloor muscle trigger points and specific areas of myofascial restrictiondetected upon palpation in a patient; the method comprising:

-   -   a) palpating a patient to detect said trigger points: and    -   b) administering to the identified trigger points of the patient        by the patient or therapist or another, a therapeutically        effective amount of a calcium channel blocker, or L-arginine, or        a combination of a calcium channel blocker and L-arginine, or        pharmaceutically acceptable salts thereof, as described in any        foregoing Method described herein.

In further embodiments, the invention provides a Method (Method 10) oftreatment or self-treatment for the reduction and/or resolution oftrigger point pain, sensitivity or activity in a muscle of a patient inneed thereof, comprising administering a therapeutically effectiveamount of a calcium channel blocker, or L-arginine, or a combination ofa calcium channel blocker and L-arginine, or pharmaceutically acceptablesalts thereof to the muscle of the patient, for example:

-   10.1. Method 10, wherein the one or more trigger points are external    trigger points.-   10.2. Method 10 or 10.1, wherein the active agent is administered by    injection.-   10.3. Method 10-10.1, wherein the active agent is administered    manually by the patient as part of a self-treatment program.-   10.4. Any Method 10-10.2 wherein the active agent is administered    directly to, near to, or adjacent to one or more trigger points of    the muscle by the patient, doctor or physical therapist.

In further embodiments, the invention provides a Method (Method 11) forrelieving external muscle soreness or pain comprising applying to themuscle a topical composition comprising a calcium channel blocker, or apharmaceutically acceptable salt thereof, for example:

-   11.1. Method 11, wherein the topical pharmaceutical composition    comprises diltiazem or nifedipine in an amount of from 0.5% to 5% by    weight.-   11.2. Method 11 or 11.1, wherein the topical pharmaceutical    composition comprises diltiazem or nifedipine in an amount of about    1%; or about 2%, or about 3%; or about 4%, or about 5% by weight.-   11.3. Any Method 11-11.2 wherein the topical pharmaceutical    composition comprises diltiazem or nifedipine in an amount of about    1% by weight.-   11.4. Any Method 11-11.3 wherein the topical pharmaceutical    composition further comprises one or more of menthol, menthone,    camphor, pulegol, isopulegol, cineole, mint oil, peppermint oil,    spearmint oil, eucalyptus oil, 3-(1-menthoxy)propane-1,2-diol,    N-alkyl-p-menthane-3-carboxamide,    2-methyl-3-(1-menthoxy)propane-1,2-diol, p-menthane-3,8-diol,    2-(1-menthoxy)ethan-1-ol, 3-(1-menthoxy)propan-1-ol,    4-(1-menthoxy)butan-1-ol, menthyl 3-hydroxybutanoate, menthyl    lactate, menthone glycerin ketal,    N-methyl-2,2-isopropylmethyl-3-methylbutane amide, menthyl    glyoxylate cajuput oil, clove oil, dementholized mint oil and    paraffin petrolatum.

In further embodiments, the invention provides a Method (Method 12) forrelieving one or more symptoms of carpal tunnel syndrome, comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising a calcium channel blocker, or a pharmaceutically acceptablesalt thereof, for example:

-   12.1. Method 12, wherein the patient is administered a topical    pharmaceutical composition in accordance with any of Compositions    1-1.7 as described herein.-   12.2. Method 12, wherein the patient is administered an oral    pharmaceutical composition in accordance with any of Compositions    2-4 as described herein.-   12.3. Method 12.1, further comprising administering a corticosteroid    with the calcium channel blocker or pharmaceutically acceptable    salts thereof.-   12.4. Method 12.3, wherein the corticosteroid is cortisone or    hydrocortisone, in an amount of from 0.01% to 5% by weight; 0.05% to    4% by weight; 0.1% to 4% by weight; 0.1% to 3% by weight; from 0.1%    to 2% by weight; or from 0.5% to 1.5% by weight, or about 0.1%,    0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4% or 5% by weight.-   12.5. Method 12, 1.1 or 12.3, wherein the topical composition is a    balm, which is massaged into the muscle.

In further embodiments, the invention provides a Method (Method 13) fortreatment of anal fissures, comprising perianal or intrarectaladministration of a topical composition comprising a calcium channelblocker, or a pharmaceutically acceptable salt thereof, for example:

-   13.1. Method 13, wherein the calcium channel blocker is nifedipine    or diltiazem.-   13.2. Method 13, wherein the calcium channel blocker is nifedipine,    and the method comprises administering a topical pharmaceutical    composition comprising nifedipine in an amount of from 0.3-2%;    wherein the topical composition comprises an excipient, which is    optionally poloxamer 407.-   13.3. Method 13, wherein the calcium channel blocker is diltiazem,    and the method comprises administering a topical pharmaceutical    composition comprising diltiazem in an amount of from 1% to 3%;    wherein the topical composition comprises an excipient, which is    optionally poloxamer 407.

In further embodiments, the invention provides a Method (Method 14) fortreatment of anal fissures, comprising oral administration of acomposition comprising a calcium channel blocker, or a pharmaceuticallyacceptable salt thereof, for example:

-   14.1. Method 14, wherein the calcium channel blocker is nifedipine    or diltiazem.-   14.2. Method 14 or 14.1, wherein the calcium channel blocker is    nifedipine, in a dose of from 1-9 mg, or from 11-19 mg, or from    21-29 mg., or from 31-89 mg.-   14.3. Method 14 or 14.1, wherein the calcium channel blocker is    diltiazem, in a dose of from 2-4 mg.

In further embodiments, the invention provides a Method (Method 15) fortreating a condition characterized by muscle spasm or sorenesscomprising administering to a patient in need thereof a therapeuticallyeffective amount of a calcium channel blocker, or L-arginine, or acombination of a calcium channel blocker and L-arginine, orpharmaceutically acceptable salts thereof, for example:

-   15.1. Method 15, wherein the condition is selected from urinary    sphincter spasms, urethral sphincter spasms, post urinary pain,    rectal sphincter spasms and proctalgia fugax.-   15.2. Method 15 or 15.1, comprising oral administration of the    calcium channel blocker, or pharmaceutically acceptable salt    thereof.-   15.3. Any Method 15-15.2, comprising administration of an extended    composition comprising the calcium channel blocker, or    pharmaceutically acceptable salt thereof.-   15.4. Any Method 15-15.3, wherein the calcium channel blocker is    selected from nifedipine and diltiazem.

In further embodiments, the invention provides a Method (Method 16) fortreating a condition selected from chronic pelvic pain, chronic pelvicpain without fissures or fistulas, chronically trigger pointed muscles,chronically trigger pointed pelvic floor muscles, chronic pelvic painsyndrome, pelvic floor myalgia, pelvic floor dysfunction, interstitialcystitis, levator ani syndrome, coccygodynia, prostatodynia, piriformissyndrome, vaginismus, anismus, anal sphincter pain, bowel movement pain,post bowel movement pain, ejaculatory pain or post ejaculatory pain;chronic pelvic pain without evidence of other pathology in external orinternal anal sphincters; pelvic pain with pain referring triggerpoints; pelvic pain with associated with pelvic floor muscle triggerpoints and/or areas of myofascial restriction; sitting pain, post bowelmovement pain, rectal pain, tailbone pain, urinary frequency, urinaryurgency, urinary hesitancy, perineal pain, penile pain, vaginismus,anismus, sexual dysfunction and reduced level of ejaculate or reducedpenile erection, urinary sphincter spasms, urethral sphincter spasms,post urinary pain, rectal sphincter spasms, proctalgia fugax andmyofascial pain in muscle tissue of a patient who has one or moretrigger points in the muscle tissue; the method comprising treating apatient in need thereof with a dilator, such as an anal, vaginal orurethral dilator (including pediatric dilators thereof), for example:

-   16.1. Method 16, wherein the dilator is an anal, vaginal, urethral    or pediatric dilator.-   16.2. Method 16, wherein the dilator has a diameter of from about ¼    inch to about 1½ inch, for example from about ¼ inch to about ¾    inch.-   16.3. Method 16, wherein more then one dilator is used.-   16.4. Method 16, wherein the method comprises progressive    transitioning from smaller sized dilators to larger sized dilators.-   16.5. Any Method 16-16.4, wherein the dilator or dilators are used    daily, twice daily or three times daily, for a period of from about    10 minutes to about 40 minutes, or about 20 minutes to about 30    minutes.-   16.6. Any Method 16-16.4, wherein the dilators are used on a single    day, or for several days, or for a week, or for one month, or for    several months.-   16.7. Any Method 16-16.4, wherein the dilators are used until    symptoms are resolved.-   16.8. Any Method 16-16.4, further comprising the administration of a    calcium channel blocker, or a pharmaceutically acceptable salt    thereof, or a pharmaceutical composition thereof, prior to use of    the dilator or dilators.-   16.9. Method 16.8, wherein the calcium channel blocker,    pharmaceutically acceptable salt thereof, or pharmaceutical    composition thereof is administered orally for example, in the form    of a pill, tablet or capsule; or topically (e.g., as a topical    composition), such as an ointment, gel or paste.-   16.10. Method 16.9, wherein the wherein the calcium channel blocker,    pharmaceutically acceptable salt thereof, or pharmaceutical    composition thereof is administered from 5 minutes to 60 minutes    prior to dilator use.-   16.11. Any Method 16-16.10, further comprising administration of an    anesthetic.-   16.12. Method 16.11, wherein the anesthetic is a component of the    pharmaceutical composition containing the calcium channel blocker.-   16.13. Any Method 16.8-16.12, wherein the calcium channel blocker is    nifedipine.-   16.14. Any Method 16.8-16.12, wherein the calcium channel blocker is    administered in an oral or topical composition according to any of    Compositions 1-5 herein.

In further embodiments, the invention provides any of the foregoingMethods 1-16, wherein the method (Method 17) further comprisesadministering a steroid with the calcium channel blocker, or L-arginine,or combination of calcium channel blocker and L-arginine, orpharmaceutically acceptable salts thereof, for example wherein thecorticosteroid is cortisone or hydrocortisone, in an amount of from0.01% to 5% by weight; 0.05% to 4% by weight; 0.1% to 4% by weight; 0.1%to 3% by weight; from 0.1% to 2% by weight; or from 0.5% to 1.5% byweight, or about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4% or 5% by weight.

In some embodiments of each of the foregoing Methods 1-17, the Methodscomprise oral administration of a Composition comprising nifedipine in adose of 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19,21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89 mg nifedipine. Insome embodiments, the Composition is an extended release composition. Insome embodiments, the composition is an immediate release composition.

In further embodiments, the invention provides the use of diltiazem,nifedipine, L-arginine or pharmaceutically acceptable salts thereof, totreat prostatitis category IIIA and/or IIIB in a male patient. Infurther embodiments, the invention provides the use of diltiazem,nifedipine, L-arginine or pharmaceutically acceptable salts thereof totreat chronic pelvic pain, chronic pelvic pain syndrome, pelvic floormyalgia, pelvic floor dysfunction, interstitial cystitis, levator anisyndrome, coccygodynia, prostatodynia, piriformis syndrome, vaginismus,anismus, anal sphincter pain, bowel movement pain, post bowel movementpain, ejaculatory pain or post ejaculatory pain.

In further embodiments, the invention provides the use of diltiazem,nifedipine, L-arginine or pharmaceutically acceptable salts thereof totreat sitting pain, post bowel movement pain, rectal pain, tailbonepain, urinary frequency, urinary urgency, urinary hesitancy, perinealpain, penile pain, sexual dysfunction and reduced level of ejaculate orreduced penile erection. In further embodiments, the invention providesthe use of diltiazem, nifedipine L-arginine or pharmaceuticallyacceptable salts thereof to treat myofascial pain in muscle tissue of apatient who has one or more trigger points in the muscle tissue.

In further embodiments, the invention provides the use of diltiazem,nifedipine, L-arginine pharmaceutically acceptable salts thereof toreduce the pain/sensitivity of pelvic floor muscle trigger pointsdetected upon palpation in a patient used topically and applied with agloved finger of the patient manually. In further embodiments, theinvention provides the use of diltiazem, nifedipine L-arginine orpharmaceutically acceptable salts thereof to treat pelvic pain in afemale patient.

In further embodiments, the invention provides a topical pharmaceuticalcomposition (Composition 1) comprising a calcium channel blocker, orL-arginine, or a combination of a calcium channel blocker andL-arginine, or pharmaceutically acceptable salts thereof, in atherapeutically effective amount, for example:

-   -   1.1. Composition 1, wherein the calcium channel blocker is        nifedipine or diltiazem.    -   1.2. Composition 1 or 1.1, further comprising a poloxamer; for        example poloxamer 407.    -   1.3. Any Composition 1-1.2, further comprising a local        anesthetic, for example lidocaine.    -   1.4. Any Composition 1-1.3, comprising diltiazem or nifedipine        in an amount of from 0.5% to 5% by weight.    -   1.5. Any Composition 1-1.4, comprising diltiazem or nifedipine        in an amount of about 1%; or about 2%, or about 3%; or about 4%,        or about 5% by weight.    -   1.6. Any Composition 1-1.5, comprising diltiazem or nifedipine        in an amount of about 1% by weight.    -   1.7. Any Composition 1-1.6, comprising L-arginine in an amount        of from 0.4% to 4% by weight.    -   1.8. Any Composition 1-1.3, comprising nifedipine or diltiazem        in an amount therapeutically effective to treat one or more of        chronic pelvic pain, chronic pelvic pain syndrome, pelvic floor        myalgia, pelvic floor dysfunction, interstitial cystitis,        levator ani syndrome, coccygodynia, prostatodynia, piriformis        syndrome, anal sphincter pain, bowel movement pain, post bowel        movement pain, vaginismus, anismus, ejaculatory pain, post        ejaculatory pain, sitting pain, post bowel movement pain, rectal        pain, tailbone pain, urinary frequency, urinary urgency, urinary        hesitancy, perineal pain, penile pain, sexual dysfunction,        reduced level of ejaculate or reduced penile erection,        myofascial pain in muscle tissue of a patient who has one or        more trigger points in the muscle tissue, conditions        characterized by muscle spasm or soreness, urinary sphincter        spasms, urethral sphincter spasms, post urinary pain, rectal        sphincter spasms and proctalgia fugax, or the pain/sensitivity        of pelvic floor muscle trigger points and specific areas of        myofascial restriction detected upon palpation in a patient

In further embodiments, the invention provides a pharmaceuticalcomposition (Composition 2) for oral administration comprisingnifedipine in an amount of from 1 to 89 mg nifedipine, for example 1, 2,3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24,25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, or 89 mg nifedipine, for example:

-   -   2.1. Composition 2, comprising nifedipine in an amount of 1, 2,        3, 4, 5, 6, 7, 8 or 9 mg.    -   2.2. Composition 2, comprising nifedipine in an amount of 11,        12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28,        29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,        46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62,        63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,        79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89 mg.    -   2.3. Composition 2, comprising nifedipine in an amount of 11,        12, 13, 14, 15, 16, 17, 18, or 19 mg.    -   2.4. Composition 2, comprising nifedipine in an amount of 21,        22, 23, 24, 25, 26, 27, 28, or 29 mg.    -   2.5. Composition 2, comprising nifedipine in an amount of 31,        32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,        48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64,        65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,        81, 82, 83, 84, 85, 86, 87, 88 or 89 mg.    -   2.6. Composition 2, comprising nifedipine in an amount of 3 mg,        5 mg, 6 mg, 9 mg, 12 mg, 15 mg, 18 mg, 21 mg, 24 mg, 25 mg, 27        mg or 29 mg of nifedipine.    -   2.7. Composition 2, comprising nifedipine in an amount of 32 mg,        35 mg, 38 mg, 40 mg, 41 mg, 45 mg, 48 mg, 50 mg, 55 mg, 58 mg,        62 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg or 89 mg of nifedipine.    -   2.8. Any Composition 2-2.7, wherein the composition is an        immediate release composition.    -   2.9. Any Composition 2-2.7, wherein the composition is an        extended release composition.

In further embodiments, the invention provides a pharmaceuticalcomposition (Composition 3) for oral administration comprising diltiazemin an amount of 1, 2, 3, 6, 12, 15, 18, 21, 24 or 27 mg diltiazem. Insome embodiments, the composition is extended release, and in otherembodiments, the composition is immediate release. In furtherembodiments, the invention provides an extended release pharmaceuticalcomposition (Composition 4) for oral administration comprising diltiazemin an amount of 1 mg to 170 mg; or 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60mg, 70 mg, 80 mg, 90 mg, 100 mg or 110 mg of diltiazem. In someembodiments, the composition is extended release, and in otherembodiments, the composition is immediate release.

In further embodiments, the invention provides a composition(Composition 5) that is an extended release, enterically coated dosageform comprising an active ingredient that is a calcium channel blocker,wherein the dosage form additionally comprises one or more mucoadhesivepolymers, and, optionally, one or more delayed release polymers, forexample:

-   -   5.1. Composition 5, comprising a poloxamer.

In some embodiments, the invention provides a method for simultaneouslydelivering a systemic-acting and locally-acting dose of a calciumchannel blocker, comprising administering to a patient in need there thedosage form of Composition 5 or 5.1.

In further embodiments, the invention provides Compositions 1-5 for usein treating pelvic pain disorders, such as prostatitis category IIIAand/or IIIB in a male patient, chronic pelvic pain, pelvic floor muscleswith trigger points or areas of myofascial restriction, chronic pelvicpain syndrome, pelvic floor myalgia, pelvic floor dysfunction,interstitial cystitis, levator ani syndrome, coccygodynia,prostatodynia, prostadynia, piriformis syndrome, anal sphincter pain,bowel movement pain, post bowel movement pain, ejaculatory pain,ejaculatory discomfort, post ejaculatory pain, sitting pain, rectalpain, tailbone pain, urinary frequency, urinary urgency, urinaryhesitancy, perineal pain, penile pain, vaginismus, anismus, sexualdysfunction, reduced level of ejaculate or reduced penile erection,nonbacterial prostatitis, slow urinary flow, reduced urinary flow, postejaculatory discomfort, urinary or urethral sphincter spasms, posturinary pain, rectal sphincter spasms, proctalgia fugax, myofascial painin muscle tissue of a patient who has one or more trigger points in themuscle tissue, and the pain/sensitivity of pelvic floor muscle triggerpoints and specific areas of myofascial restriction detected uponpalpation in a patient.

The invention further provides each of the foregoing Methods 1-17,comprising administration of any foregoing Composition as describedherein, e.g., Composition 1-5.1.

In some embodiments of each of the Methods 1-17 described herein, themethods further comprise the step of identifying a patient in need ofsaid treatment.

In some embodiments of each of the Methods 1-17 described herein, themethods further comprise administration of an anesthetic, an anesthetic,for example a local anesthetic, for example lidocaine.

In some embodiments of each of the topical Compositions 1-1.8 and 5-5.1described herein, the compositions can further comprise an anesthetic,for example a local anesthetic, for example lidocaine.

The present invention also provides an apparatus (Apparatus 1) forapplying a topical pharmaceutical composition to a treatment site thatis located within a rectal cavity or a vaginal cavity of a humanpatient, the apparatus comprising: a tubular member, wherein the topicalpharmaceutical composition is located inside the tubular member prior toapplication of the topical preparation to the treatment site; and anapplicator member that is receivable in the sleeve wherein, theapplicator member is movable within the tubular member from a firstposition to a second position to cause at least a portion of the topicalpreparation to be moved out of the sleeve and thereby applied to thetreatment site, for example:

-   -   1.1. Apparatus 1, wherein the tubular member is adapted to        extend into an opening of the rectal cavity or the vaginal        cavity of the human patient.    -   1.2. Apparatus 1, wherein the tubular member extends from a        first end to a second end, wherein the first end is disposed        within the rectal cavity or the vaginal cavity of the human        patient during application of the topical pharmaceutical        composition to the treatment site and the second end is disposed        outside of the rectal cavity or the vaginal cavity of the human        patient during application of the topical pharmaceutical        composition to the treatment site.    -   1.3. Apparatus 1, wherein the tubular member extends from a        first end to a second end, wherein the first end is disposed        within the rectal cavity or the vaginal cavity of the human        patient during application of the topical pharmaceutical        composition to the treatment site and the second end is disposed        outside of the rectal cavity or the vaginal cavity of the human        patient during application of the topical pharmaceutical        composition to the treatment site.    -   1.4. Apparatus 1.3, wherein the first end has a semi-spherical        configuration defined by a plurality of segments that are        movable in response to movement of the applicator member from        the first position to the second position.    -   1.5. Apparatus 1, further comprising a stop surface that extends        outward from the tubular member for restraining further        insertion of the tubular member with respect to the rectal        cavity or the vaginal cavity of the human patient.

The present invention also provides an apparatus (Apparatus 2) which isa drug applicator sleeve, the sleeve comprising:

-   -   a tubular member having an open end and a closed end; and    -   an integral conduit disposed thereon or therein;    -   wherein:    -   the tubular member has a length of from 2 to 10 inches, and a        diameter of from ⅛ to 2 inches;    -   the integral conduit has a diameter of from ⅙ inch to 1 inch,        and also optionally comprises a receiver for interfacing with a        syringe, bulb or other reservoir, for example:

Further examples of Apparatus 2 according to the present inventioninclude:

-   -   2.1. Apparatus 2, wherein the drug delivery sleeve is a smooth        tube.    -   2.2. Apparatus 2 or 2.1, wherein the drug delivery sleeve is        adapted to conform to the surfaces of a probe or trigger point        wand.    -   2.3. Any apparatus 2-2.2, wherein the integral conduit comprises        a receiver for interfacing with a syringe, bulb or other        reservoir.    -   2.4. Any apparatus 2-2.3, wherein the integral conduit is        prefilled with a pharmaceutical composition.    -   2.5. Apparatus 2.4, wherein the pharmaceutical composition is a        Composition according to any of Compositions 1-5 described        herein.    -   2.6. Any apparatus 2-2.5, wherein the integral conduit is        disposed substantially along the length of the sleeve.

In further embodiments, the invention provides an assembly comprising amedical probe or trigger point wand and a drug applicator sleeveaccording to any of Apparatus 2-2.6.

In further embodiments, the invention provides kits comprising adisposable rectal syringe and a pharmaceutical composition according toany of Compositions 1-1.7. In further embodiments, the inventionprovides kits comprising a re-useable rectal syringe and apharmaceutical composition according to any of Compositions 1-1.7. Infurther embodiments, the invention provides kits comprising anapplicator as described herein, and a pharmaceutical compositionaccording to any of Compositions 1-1.7. In some embodiments, the syringeor applicator of the kit is pre-filled with the pharmaceuticalcomposition.

In some further embodiments, the invention provides kits comprising aplurality of dilators having sizes from about ¼ inch in diameter toabout 1½ inch in diameter, or about ¼ inch in diameter to about ¾ inchin diameter, in size increments of 1/16 inch or ⅛ of an inch. In someembodiments, the kits further comprising an application guide, whichprovides instructions regarding the use of the dilators.

-   -   The following examples are further illustrative of the nature of        the present invention, but it is understood that the invention        is not limited thereto. All amounts and proportions referred to        herein and in the appended claims are by weight, unless        otherwise indicated.

Example 1—Preparation of Topical Formulation

Three ointment formulations are prepared that contain 1% diltiazem,0.2-2% nifedipine and 1% L-arginine respectively as the activeingredient, each in an ointment containing poloxamer 407, and paraffin,or a transdermal vehicle or cream as known in the art for use as acarrier for active substances administered to the inside the anus orrectum.

Example 2—Preparation of Suppository Formulation

A base is prepared containing hydrogenated vegetable oil and PEG-8Distearate. An appropriate amount of the base is weighed out and meltedover low heat. Active (1% diltiazem or 0.2-2% nifedipine and/or 1%L-arginine) is weighed out. Silica gel is added and the combination issifted into the melted base. The composition is then poured intosuppository molds and cooled.

Example 2—Determination of Pelvic Floor Muscle Trigger Points andSpecific Areas of Myofascial Restriction

A patient's history is taken and the patient's pelvic pain relatedcomplaints are noted. A physical examination by a professionalexperienced in identifying and treating trigger points is done withknowledge of which trigger points are generally related to particularcomplaints. The professional then puts on an examining glove andexamines tissue inside the anal sphincter and rectum of both men andwomen and inside the vagina in women, pressing on areas known to berelated to particular symptoms. When a trigger point is felt (a tenderband), a twitch is felt, the patient exhibits a ‘jump response’ and thesymptom that the patient complains about is recreated, the trigger pointis noted. The patient is later directed to apply nifedipine ointment, ordiltiazem ointment, or L-arginine ointment for example in the area wheretrigger points were found.

Example 3—Administration of Topical Formulation

The topical formulation is administered to the patient's trigger pointsdetermined in example 2 above either manually, using a rectal syringe,or using the internal trigger point wand as described in, e.g. U.S. Pat.Nos. 8,337,435 and 8,224,464.

Example 4—Use of Dilators

Not wishing to be bound by any particular theory, pelvic pain,manifesting symptoms described in this application, is believed to beintimately related to the myofascial irritability, trigger points andareas of spasm in the pelvic floor. This can come from an injury orchronic tightening of the pelvic floor, not unlike an animal pulling itstail between its legs and tightening the pelvic floor in doing so, thatwith our without hypertonus, creates a constricted pelvic environment inwhich the shortened tissue in the pelvic floor and the resultant triggerpoints and areas of myofascial restriction refer pain to a variety ofsites remote from the area of myofascial restriction. This can result ina ischemia in which blood flow is reduced in the sphincter, vaginalopening and pelvic floor. Nifedipine reduces calcium in the calciumchannels and thereby relaxes the tissue, increases blood flow andreduces trigger point activity in the tissue.

What can augment the lengthening and rehabilitation of pelvic floor, thereduction of trigger points and the reduction of symptoms is the gradualmicroscopic lengthening of the contracted pelvic tissue with the use ofa myofascial release aid called an anal and vaginal dilator. The dilatorintroduces in very small increments, a device that slowly stretches thesphincter and vagina from its hyperirritable and guarded state in a waythat the sphincter and vagina can tolerate. Dilators of ¼″ diameter areeasily tolerated by the most hyperirritable orifices of a guarded analsphincter or vaginal opening, and leaving the dilator in the orifice for5-30 minutes while the patient practices relaxation of the area, in ourclinical experience with certain patients, can give the patient a veryclear sense of their own guarding and makes it easier for the patient torelax the guarded pelvic floor. The relaxation of this guardingtypically leads to the release of the pelvic muscle spasm, the releaseof pelvic floor trigger points and the reduction of pain and symptoms.Once the sphincter is able to tolerate a very small diameter dilator,the next very small increment of size dilator is used. In a very painfuland highly guarded anal sphincter or vagina, the progression of dilatorschanges every 3-4 weeks from ½″ to ⅜″ to ½″, to ⅝″ to ¾″ to ⅞″ to 1 inchto 1⅛ inch to 1¼ inch to 1⅜ in to 1½ inch. This slow increase in thestretch of the pelvic opening is under the patients control and isgenerally well tolerated and give the patient a sense of control overrehabilitation of their pelvic muscles. In combination with hot baths,the use of nifedipine, very gradual, non traumatic dilation andrelaxation to lower autonomic arousal, progressive dilation is apowerful adjunct to the rehabilitation of a sore and painful pelvicfloor.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiments, but to the contrary, it is intended to covervarious modifications or equivalent arrangements included within thespirit and scope of the appended claims. The scope is to be accorded thebroadest interpretation so as to encompass all such modifications andequivalent structures as is permitted under the law.

Each of the patents, books, articles and other printed publicationsreferenced herein are incorporated by reference in their entireties forall purposes.

1-73. (canceled)
 74. A method for treatment of anal fissures, comprisingperianal or intrarectal administration of a topical compositioncomprising a calcium channel blocker, or a pharmaceutically acceptablesalt thereof.
 75. The method of claim 74, wherein the calcium channelblocker is nifedipine or diltiazem in a dose of from 1-29 mg.
 76. Amethod for treatment of anal fissures, comprising oral administration ofa pharmaceutical composition comprising a calcium channel blocker, or apharmaceutically acceptable salt thereof.
 77. The method of claim 76,wherein the calcium channel blocker is nifedipine or diltiazem in a doseof from 1-29 mg.
 78. The method of claim 76, wherein the calcium channelblocker is nifedipine, and the method comprises administering a topicalpharmaceutical composition comprising nifedipine in an amount of from0.3-2%; wherein the topical composition comprises an excipient, which isoptionally poloxamer
 407. 79-101. (canceled)